KR20140027918A - Neprilysin inhibitors - Google Patents

Abstract

식 중에서, R¹-R⁶, a, b, 및 X는 상세한 설명에 정의된 것과 같다. 이러한 화합물은 네프릴리신 억제 활성을 갖는다. 다른 양태에서, 본 발명은 그와 같은 화합물을 포함하는 약학적 조성물; 그와 같은 화합물을 사용하는 방법; 및 그와 같은 화합물을 제조하는 방법 및 중간체에 관한 것이다.In one aspect, the invention relates to a compound having the formula: or a pharmaceutically acceptable salt thereof:

Wherein R ¹ -R ⁶ , a, b, and X are as defined in the detailed description. Such compounds have a nephrillosine inhibitory activity. In another aspect, the present invention provides a pharmaceutical composition comprising such a compound; A method of using such a compound; And methods and intermediates for the preparation of such compounds.

Description

Neprilysin inhibitors

The present invention relates to novel compounds having nephrilline-inhibiting activity. The invention also relates to pharmaceutical compositions comprising such compounds, methods and intermediates for making such compounds, and methods of using such compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension and kidney disease.

Nephralinopeptidase (EC 3.4.24.11) (NEP) is an endothelial membrane-bound Zn found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart and peripheral vasculature. ^{2 +} metal is a peptidase. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides and natriuretic peptides, and the latter, for example, It has several effects including vasodilation and natriuresis / dieresis as well as cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.

NEP inhibitors, such as thiorphan, candoxatril and candoxatrilat, have been studied as potential therapeutics. Compounds that inhibit both NEP and angiotensin-I converting enzyme (ACE) are also known and include omapatrilat, gempatrilat and sampatrilat. The latter compounds, referred to as the vasopeptidase inhibitors, are described by Robl et al. (1999) Exp . Opin . Ther . Patents 9 (12): 1665-1677.

The present invention provides novel compounds that have been found to have neprilysin (NEP) enzyme inhibitory action. Accordingly, the compounds of the present invention are expected to be useful and advantageous as therapeutic agents for treating diseases such as hypertension and heart failure.

One aspect of the invention is directed to a compound of formula I: < EMI ID =

In the formula:

R ¹ is selected from -OR ⁷ and -NR ⁸ R ⁹ ;

R ² is H or —P (O) (OH) ₂ , or R ² together with R ⁷ forms —CR ¹⁸ R ¹⁹ — or together with R ⁸ forms —C (O) —;

X is -C _{1 - 9} heteroaryl;

R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -NO ₂ ; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl optionally substituted with methyl; Thiophenyl optionally substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl; When R ³ is present it is bonded to a carbon atom;

R ⁴ is absent or H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -OCH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -OCH ₂ OC (O) CH ₃ ; -CH ₂ OP (O) (OH) ₂ ; -CH ₂ CH (OH) CH ₂ OH; _{-CH [CH (CH 3) 2} ] -NHC (O) OC 1 - 6 alkyl; Pyridinyl; And phenyl or benzyl optionally substituted with one or more groups selected from halo, -COOR ³⁵ , -OCH ₃ , -OCF ₃ , and -SCF ₃ ; When R ⁴ is present it is bonded to a carbon or nitrogen atom;

Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- ;

a is 0 or 1; R ⁵ is selected from halo, —CH ₃ , —CF ₃ , and —CN;

b is 0 or an integer from 1 to 3; Each R ⁶ is independently selected from _{halo, -OH, -CH 3, -OCH 3} , and -CF _3;

R ⁷ is H, -C _{1 - 8} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - _{[(CH 2) 2 O]} 1-3 CH 3, -C 1 - 6 alkylene group ^{-OC (O) R 10, -C} 1 - 6 alkylene _{^{-NR 12 R 13, -C 1 -}} 6 alkylene- ^{C (O) R 31, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

,

, 및

으로부터 선택되고;

,

,

, And

≪ / RTI >

R ¹⁰ is -C _{1 - 6} alkyl, -OC _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -OC _{3 - 7} cycloalkyl, phenyl, -O- ^{phenyl, -NR 12 R 13, -CH [} CH _{(CH 3) 2] -NH 2} , -CH [CH (CH 3) 2] -NHC (O) OC 1 - 6 alkyl, and -CH (NH ₂₎ CH ₂ COOCH ₃ is selected from; R ¹² and R ¹³ are independently selected from H, -C _{1 - 6,} or selected from alkyl, and benzyl; Or R ¹² and R ¹³ together form — (CH ₂ ) _3-6 —, —C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —; R ³¹ is -OC _{1 - 6} alkyl, -O- benzyl, and is selected from -NR ¹² R ^13; R ³² is -C _{1 - 6} alkyl, -C _{0 - 6} alkylene -C _{6 - 10} aryl;

R ⁸ is selected from H, —OH, —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, -pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ¹⁴ is H, -C ₁₆ alkyl, -C _{6 - 10} aryl, -OCH ₂ -C _{6 - 10} aryl, -CH ₂ OC _{6 - 10} aryl, and is selected from -NR ¹⁵ R ^16; R ¹⁵ and R ¹⁶ are independently selected from H and -C _{1 -} is selected from _4-alkyl;

R ⁹ is H, -C _{1 - 6} alkyl, and -C (O) is selected from -R ^17; R ¹⁷ is H, -C _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -C _{6 - 10} aryl, and -C _{1 - 9} is selected from heteroaryl;

R ¹⁸ and R ¹⁹ are independently selected from H, -C _{1 -} to form a _seven or selected from cycloalkyl, or R ¹⁸ and R ¹⁹ together are = O _{- 6} alkyl, and -OC _3;

R ²⁰ is selected from H and -C _{1 - 6} alkyl is selected from;

R ²¹ and R ³⁵ are independently selected from H, -C _{1 - 6} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7 cycloalkyl, - [(CH 2) 2} O] 1-3 CH 3, -C 1 - 6 alkylene group -OC (O) R ^25; -C _{1 - 6} alkylene _{^{-NR 27 R 28, -C 1 -}} 6 alkylene ^{-C (O) R 33, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ - C _{1 - 6} alkyl,

,

,

, 및

으로부터 선택되고;

,

,

, And

≪ / RTI >

R ²⁵ is -C _{1 - 6} alkyl, -OC _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -OC _{3 - 7} cycloalkyl, phenyl, -O- ^{phenyl, -NR 27 R 28, -CH [} CH _{(CH 3) 2] -NH 2} , -CH [CH (CH 3) 2] -NHC (O) OC 1 - 6 is selected from alkyl, and _{-CH (NH 2) CH 2 COOCH} 3; R ²⁷ and R ²⁸ are independently selected from H, -C _{1 - 6,} or selected from alkyl, and benzyl; Or R ²⁷ and R ²⁸ together form — (CH ₂ ) _3-6 —, —C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —; R ³³ is -OC _{1 - 6} alkyl, -O- benzyl, and -NR ²⁷ R ²⁸ is selected from; R ³⁴ is -C _1-6 alkyl, -C _{0 - 6} alkylene -C _{6 - 10} aryl;

R ²² and R ²³ are independently selected from H, -C _{1 - 6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH; _{- (CH 2) 2 OCH 3} , - (CH 2) 2 SO 2 NH 2, - (CH 2) 2 N (CH 3) 2, -C 0 - 1 alkylene -C _{3 - 7} cycloalkyl, and - (CH ₂ ) ₂ -imidazolyl; Or R ²² and R ²³ together is halo, -OH, -COOH, or optionally substituted, saturated or partially unsaturated, the -C ₃ substituted with -CONH _{2 - 5} form a heterocycle, and; Optionally include an oxygen atom in the ring;

R ²⁴ is -C _{1 - 6} alkyl; -C _{0 - 1} alkylene -OC _{1 - 6} alkyl; Phenyl optionally substituted with halo or -OCH ₃ ; And -C _{1 - 9} is selected from heteroaryl;

R ³⁶ is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl;

Wherein each alkyl group of R ¹ , R ³ , and R ⁴ is optionally substituted with 1 to 8 fluorine atoms; And;

The methylene linking groups on the biphenyl is one or two -C _{1 - 6} alkyl group is optionally substituted by or cyclopropyl.

Another aspect of the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention. Such compositions may optionally include other therapeutic agents. Accordingly, in another embodiment of the present invention, the pharmaceutical composition comprises a compound of the present invention which is a first therapeutic agent, one or more second therapeutic agents, and a pharmaceutically acceptable carrier. Another aspect of the invention relates to a combination of active agents comprising a compound of the invention and a second therapeutic agent. The compounds of the present invention may be formulated together or separately with additional agents. When formulated separately, pharmaceutically acceptable carriers may be included with additional agent (s). Accordingly, another aspect of the present invention relates to a combination of pharmaceutical compositions, the combination comprising a first pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable first carrier; And a second pharmaceutical composition comprising a second therapeutic agent and a second pharmaceutically acceptable carrier. In another aspect, the invention relates to a kit comprising such a pharmaceutical composition, for example, wherein the first and second pharmaceutical compositions in the kit are separate pharmaceutical compositions.

The compounds of the present invention have NEP enzyme inhibitory activity and are therefore expected to be useful as therapeutics for treating patients with diseases or disorders that are treated by inhibiting the NEP enzyme or increasing the level of the peptide substrate thereof. Accordingly, one aspect of the present invention relates to a method of treating a patient suffering from a disease or disorder treated by inhibiting an NEP enzyme, comprising administering to the patient a therapeutically effective amount of a compound of the present invention. Another aspect of the invention relates to a method of treating hypertension, heart failure or kidney disease, comprising administering to a patient a therapeutically effective amount of a compound of the invention. Another aspect of the present invention is directed to a method of inhibiting NEP enzyme in a mammal comprising administering to a mammal a NEP enzyme-inhibiting amount of a compound of the present invention will be.

The compounds of the present invention have NEP inhibitory activity and are therefore also useful as research tools. Accordingly, one aspect of the invention relates to a method of using a compound of the invention as a research tool, comprising the step of performing a biological assay using a compound of the invention. The compounds of the present invention can also be used to evaluate new chemical compounds. Accordingly, another aspect of the present invention is directed to a method of evaluating a test compound in a biological assay, the method comprising the following steps: (a) performing a biological assay with a test compound to provide a first assay value ; (b) conducting a biological assay with a compound of the present invention to provide a second assay value; Step (a) is performed before, after or simultaneously with step (b); And (c) comparing the first analysis value obtained from step (a) with the second analysis value obtained from step (b). Exemplary biological assays include NEP enzyme inhibition assays. Another aspect of the invention relates to a method of studying a biological system or sample comprising a NEP enzyme, the method comprising: (a) contacting the biological system or sample with a compound of the invention; And (b) determining the effect of the compound on the biological system or sample.

Another aspect of the present invention relates to methods and intermediates useful in preparing the compounds of the present invention. Accordingly, another aspect of the present invention relates to a method for preparing a compound of formula I, comprising coupling a compound of formula 1 with a compound of formula 2 to produce a compound of formula I:

;

;

Wherein P ¹ is an amino-protecting group selected from H or t -butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t -butyldimethylsilyl ; And the method further comprises deprotecting the compound of formula 1 when P ¹ is an amino protecting group; Wherein R ¹ -R ⁶ , a, b, and X are as defined for Formula (I). Another aspect of the invention relates to a process for preparing a pharmaceutically acceptable salt of a compound of formula (I) comprising the step of contacting a free acid or free form of a compound of formula (I) with a pharmaceutically acceptable base or acid. In another aspect, the invention relates to products made by one of the methods disclosed herein and to novel intermediates used in such methods. In one aspect of the invention, the novel intermediate has Formula 1, 6, 7, 8, or 9, or salts thereof, as defined herein.

Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, in particular for the preparation of a medicament useful for treating hypertension, heart failure or kidney disease. Another aspect of the invention relates to the use of a compound of the invention for inhibiting a NEP enzyme in a mammal. Another aspect of the invention also relates to the use of the compounds of the invention as a means of research. Other aspects and embodiments of the invention are disclosed herein.

Justice

When describing the compounds, compositions, methods, and methods of preparation of the invention, the following terms have the following meanings, unless otherwise specified. Also, as used herein, the singular forms “a, an” and “the” include corresponding plural forms unless the context in which they are used is expressly stated otherwise. The terms " comprising, "and" having "are intended to be inclusive and mean that there may be additional elements other than the listed elements. All numbers expressing characteristics such as amount of ingredients, molecular weight, reaction conditions, etc. used in the present specification are understood to be modified by the term "about " in all cases unless otherwise stated. Thus, the numbers set forth herein are approximations that may vary depending upon the desired properties to be obtained by the present invention. At the very least, and without intending to limit the application of the doctrine of equivalents to the scope of the claims, each number should at least be construed in light of the reported significant digits and applying ordinary rounding techniques.

The term "alkyl" means a monovalent saturated hydrocarbon group, which may be linear or branched. The alkyl group is generally from 1 to and including 10 carbon atoms, for example, -C ₁ unless otherwise defined _{- 4} alkyl, -C _{1 - 5} alkyl, -C _{2 - 5} alkyl, -C _{1 - 6} It includes alkilreul _{10 -alkyl,} -C _{1 - 8} alkyl, and -C _1. Representative alkyl groups include, for example, methyl, ethyl, n - propyl, isopropyl, n - butyl, s - butyl, isobutyl, t - butyl, n - pentyl, n - hexyl, n - heptyl, n - octyl, n - nonyl, n -decyl, and the like.

When a particular number of carbon atoms is intended for a particular term used herein, the number of carbon atoms is indicated in front of the term as a subscript. For example, the term cycloalkyl group, each having _{- - "7} cycloalkyl, -C _3" is 3 to 7 carbon atoms _"1 -C ₆ alkyl" means one to six alkyl groups having carbon atoms, the term Meaning that the carbon atoms are present in any acceptable configuration.

The term "alkylene" means a divalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, the alkylene group is generally, for example, contain 0-10 carbon atoms, -C _{0 - 1} alkylene _-, -C ₀ - ₆ alkylene _-, -C ₁ - ₃ alkylene - it includes -, and -C _{1 -6} alkylene. Representative alkylene groups include, for example, methylene, ethane-1,2-diyl ("ethylene"), propane-1,2-diyl, propane- 1,5-diyl, and the like. The term alkylene -C _{0 - 1} alkylene- when they contain carbon, such as 0, that term is if the carbon atom members, that is, is an alkylene, except that the covalent bond attaching the groups separated by the alkylene term It is intended to include cases where no groups are present.

The term "aryl" refers to a monovalent aromatic hydrocarbon having a single ring (ie phenyl) or one or more condensed rings. Condensed ring systems include those that are fully unsaturated (eg naphthalene) and partially unsaturated (eg 1,2,3,4-tetrahydronaphthalene). Unless otherwise defined, such aryl groups, and contain a generally 6 to 10 ring carbon atoms, such as -C _{6 -} comprises ₁₀ ahrilreul. Representative aryl groups include, for example, phenyl and naphthalen-1-yl, naphthalen-2-yl and the like.

The term "cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group. It comprises ₆ cycloalkyl and -C _{3 -7} cycloalkyl _{alkilreul-one,} and such cycloalkyl group is generally 3 to 10 carbon atoms includes, for example, -C ₃ unless otherwise defined _{- 5} cycloalkyl, -C ₃ . Representative cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "halo" means fluoro, chloro, bromo and iodo.

The term “heterocycle” is intended to include monovalent unsaturated (aromatic) heterocycles having a single ring or two condensed rings, and monovalent saturated and partially unsaturated groups having a single ring or a plurality of condensed rings. The heterocycle ring may comprise a total of 3 to 15 ring atoms, of which 1 to 14 are ring carbon atoms and 1 to 4 are ring heteroatoms selected from nitrogen, oxygen or sulfur. In general, however, heterocycle rings contain a total of 3 to 10 ring atoms, of which 1 to 9 are ring carbon atoms and 1 to 4 are ring heteroatoms. The attachment site is at any available carbon or nitrogen ring atom. Exemplary heterocycles, for example, -C _{1 - 7} heterocycle, -C _{3 - 5} heterocycle, -C _{2 - 6} heterocycle, -C _{3 -12} heterocycle, -C _{5 - 9} heterocycle, -C ₁ includes a _{14 heterocycle-9} heterocyclyl, -C _{1 - 11} heterocyclyl, and -C _1.

A monounsaturated heterocycle is also commonly referred to as a "heteroaryl" group. Unless defined otherwise, heteroaryl groups generally comprise a total of 5 to 10 ring atoms, of which 1 to 9 are ring carbon atoms and 1 to 4 are ring heteroatoms, for example -C _{1 -} it includes the _{9 heteroaryl- 9} heteroaryl and -C _5. Representative heteroaryl groups include, for example, pyrrole (eg, 3-pyrrolyl and 2H-pyrrole-3-yl), imidazole (eg, 2-imidazolyl), furan (eg, 2- Furyl and 3-furyl), thiophene (eg 2-thienyl), triazoles (eg 1,2,3-triazolyl and 1,2,4-triazolyl), pyrazoles (eg For example, 1H-pyrazol-3-yl), oxazole (eg 2-oxazolyl), isoxazole (eg 3-isoxazolyl), thiazole (eg 2-thia Zolyl and 4-thiazolyl), and isothiazole (eg 3-isothiazolyl), pyridine (eg 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyridyl Midazole, pyridyltriazole, pyrazine, pyridazine (eg 3-pyridazinyl), pyrimidine (eg 2-pyrimidinyl), tetrazole, triazine (eg 1, 3,5-triazinyl), indolyl (eg 1H-indol-2-yl, 1H-indol-4-yl and 1H-indol-5-yl), benzofuran (eg benzofuran- 5 days) , Benzothiophene (eg benzo [b] thien-2-yl and benzo [b] thien-5-yl), benzimidazole, benzoxazole, benzothiazole, benzotriazole, quinoline (eg 2-quinolyl), isoquinoline, quinazoline, quinoxaline and the like.

Monovalent saturated heterocycle typically contains a total of from 3 to 10 ring atoms, and from 2 to 9 of which is a ring carbon atom, 1 to 4 are ring heteroatoms, e.g., -C _{3 - 5} hetero It includes a cycle. Representative monovalent saturated heterocycles include, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline and the like. Includes monovalent species. In some instances, the moiety (moiety) optionally, saturation -C ₃ containing an oxygen atom in the ring together _may be described as forming a heterocyclic _5. Such groups include:

,

,

, 및

.

,

,

, And

.

1 is generally include a total of 3 to 10 ring atoms, 2 to 11 of which is a ring carbon atom, 1 to 3 are hetero ring atoms, for example ₃ -C partially unsaturated heterocyclic _{5 12} includes _{heterocyclic-heterocyclic,} and -C _2. Representative monovalent partially unsaturated heterocycles include, for example, pyran, benzopyran, benzodioxol (eg, benzo [1,3] dioxol-5-yl), tetrahydropyridazine, 2,5-dihydro -1H-pyrrole, dihydroimidazole, dihydrotriazole, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrooxadiazole, dihydrothiadiazole, tetrahydro Pyridazine, hexahydropyrroloquinoxaline, and dihydrooxadiazabenzo [e] azulene. In some examples, the moieties together, partially unsaturated, -C _{3 -} can be described as forming a heterocyclic _5. Such groups include:

The term " optionally substituted "means that the group may be unsubstituted or substituted once or several times, such as 1 to 3 times or 1 to 5 times or 1 to 8 times. For example, a phenyl group "optionally substituted" with a halo atom may be unsubstituted or contain 1, 2, 3, 4, or 5 halo atoms; An alkyl group "optionally substituted" with a fluorine atom may be unsubstituted or contain 1, 2, 3, 4, 5, 6, 7, or 8 fluorine atoms. Similarly, one or two -C _{1 - 6} alkyl group in "an optionally substituted" group is unsubstituted or one or two -C _{1 - 6} alkyl group may include a.

As used herein, the phrase "having the formula" or "having the structure" is not intended to be limiting, and the term "comprising" is commonly used Used in the same way. For example, once a structure is depicted, it is understood that all stereoisomers and tautomeric forms are included unless otherwise stated.

The term "pharmaceutically acceptable" when used in the present invention refers to a substance that is not biologically or otherwise unacceptable. For example, the term “pharmaceutically acceptable carrier” is incorporated into a composition without causing an unacceptable biological effect or interacting with the other ingredients in the composition in an unacceptable manner. And substances that can be administered to a patient. Such pharmaceutically acceptable substances generally include substances that meet the standard conditions required for toxicological and manufacturing tests and are recognized as appropriate inactive ingredients by the U.S. Food and Drug Administration (FDA).

The term “pharmaceutically acceptable salt” refers to salts prepared from an acceptable base or acid for administration to a patient, such as a mammal (eg, in a given dosage regimen). Salts with possible mammalian safety). However, it is understood that the salts included in the present invention are not required to be pharmaceutically acceptable salts, such as salts of intermediate compounds not intended for patient administration. Pharmaceutically acceptable salts may be derived from pharmaceutically acceptable inorganic or organic bases, and from pharmaceutically acceptable inorganic or organic acids. In addition, when the compound of formula (I) contains both basic moieties such as amines, pyridines or imidazoles and acidic moieties such as carboxylic acids or tetrazole, zwitterions may be formed, which As used herein, the term "salt" is included within the scope. Salts derived from pharmaceutically acceptable inorganic bases include ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, Primary manganous salts, potassium salts, sodium salts, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts derived from organic bases such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine ), Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine ), N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucose, But are not limited to, methylglucamine, morpholine, piperazine, piperadine, polyamine resin, procaine, purine, theobromine, triethylamine triethylamine, trimethylamine, tripropylamine, Secondary, and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines, etc., such as tromethamine, and the like. ≪ / RTI > Salts derived from pharmaceutically acceptable inorganic acids include those derived from inorganic acids such as boric acid, carbonic acid, hydrohalic (hydrobromic, hydrobromic, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic acid and salts of sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include aliphatic hydroxyl acids (e.g. citric acid, gluconic acid, glycolic acid, lactic acid, lactobio acids, maleic acid and tartaric acid), aliphatic monocarboxylic acids (e.g. Acetic acid, butyric acid, formic acid, propionic acid and trifluoroacetic acid), amino acids (e.g. aspartic acid and glutamic acid), aromatic carboxylic acids (e.g. benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid) acid), hipuric acid, and triphenylacetic acid), aromatic hydroxyl acids (eg o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid And 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acid (eg, fumaric acid, maleic acid, oxalic acid and succinic acid), glucononic acid, mandelic acid, muic acid, nicotinic acid, orotic acid, Pamoic acid, pantothenic acid, sulfonic acid ( For example, benzenesulfonic acid, camphorsulfonic acid, edicylic acid, ethanesulfonic acid, isethionic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p- Toluenesulfonic acid), xinafoic acid and the like.

As used herein, the term “prodrug” refers to the inactivity of a drug, which is converted under physiological conditions, for example, into its active form in the body, by a normal metabolic process. Or significantly less active). Such a compound may not have pharmacological activity in NEP but may be administered either orally or parenterally and then metabolized in the body to form a pharmacologically active compound in NEP . An exemplary prodrug is C _{1 - 6} alkyl esters include esters, such as _{- 6} alkyl esters and aryl -C _1. In one embodiment, the active compound has free carboxyl and the prodrug is an ester derivative thereof, ie the prodrug is an ester such as C (O) OCH ₂ CH ₃ . Such ester prodrugs are then converted by solvolysis or under physiological conditions to become free carboxyl compounds. The term is also intended to include certain protected derivatives of the compounds of formula (I) which may be prepared before the final deprotection stage. Accordingly, all protected derivatives and prodrugs of formula I are included in the scope of the present invention.

The term "therapeutically effective amount" means an amount sufficient to achieve treatment, when administered to a patient in need thereof, ie the amount of drug necessary to achieve the desired therapeutic effect. For example, a therapeutically effective amount for treating hypertension is, for example, the amount of compound needed to alleviate, inhibit, eliminate or prevent the symptoms of hypertension, or to treat the underlying cause of hypertension. In one embodiment, the therapeutically effective amount is the amount of drug required to lower blood pressure or the amount of drug required to maintain normal blood pressure. On the other hand, the term “effective amount” means an amount sufficient to achieve a desired result, which does not necessarily need to be a therapeutic result. For example, when studying a system comprising a NEP enzyme, an "effective amount" may be the amount necessary to inhibit the enzyme.

As used herein, the term "treating, treatment" refers to the treatment of a disease or medical condition (such as hypertension) in a patient, such as a mammal (especially a human), and one or more of It includes: (a) preventing the occurrence of a disease or medical condition, ie preventing the recurrence of the disease or medical condition or prophylactic treatment of a patient pre-disposed to the disease or medical condition; (b) ameliorating the disease or medical condition, ie, removing or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, ie, slowing or arresting the progression of the disease or medical condition in a patient; Or (d) alleviate the symptoms of a disease or medical condition in a patient. For example, the term “treating hypertension” includes preventing the development of hypertension, improving hypertension, suppressing hypertension, and alleviating symptoms of hypertension (eg, lowering blood pressure). The term “patient” refers to a mammal, such as a human, and a compound of the present invention, which is in need of treatment or disease prevention or is currently being treated for disease prevention purposes or for the treatment of a particular disease or medical condition, or It is intended to include test subjects used in the assay, for example animal models.

All other terms used herein are intended to have the general meaning understood by those skilled in the art to which they apply.

In one aspect, the present invention relates to a compound of formula I: < EMI ID =

As used herein, the term “compound of the invention” includes all compounds encompassed by Formula I, such as the species embodied in Formulas Ia-d, and by Formulas II and III. It includes a compound and its species. In addition, the compounds of the present invention include basic or acidic groups (eg, amino or carboxyl groups), and such compounds may therefore exist in the form of free bases, free acids, or various salts. All such salt forms are included within the scope of the present invention. In addition, the compounds of the present invention may exist as prodrugs. Thus, those skilled in the art will refer to compounds of the present specification, eg, "compounds of the present invention" or "compounds of Formula I", unless otherwise specified, as well as the compounds of Formula I as well as pharmaceutically It will be appreciated that it includes acceptable salts and prodrugs. Further, the term “or a pharmaceutically acceptable salt and / or prodrug thereof” refers to all permu of salts and prodrugs, such as pharmaceutically acceptable salts of prodrugs. It is intended to include permutation. Solvent compounds of the compounds of formula (I) are also within the scope of the present invention.

The compounds of formula I may contain one or more chiral centers, and thus such compounds may be prepared and used in various stereoisomeric forms. Accordingly, the present invention also relates to racemic mixtures, pure stereoisomers (eg, enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. It is understood herein that when a chemical structure is depicted without an indication of stereochemistry, all possible stereoisomers are included by such structure. Thus, for example, the terms "compound of formula I", "compound of formula II" and the like are intended to include all possible stereoisomers of the compound. Likewise, where a particular stereoisomer is indicated or referred to herein, it is to be understood that minor amounts of other stereoisomers, unless otherwise specified, may be present in the compositions of the present invention, provided that utility as a whole composition is not lost due to the presence of other isomers Lt; / RTI > Individual stereoisomers are obtained by a number of methods well known in the art, for example by chiral chromatography using suitable chiral stationary phases or supports, or chemically converting them to diastereomers, followed by chromatography or recrystallization and After separation of the diastereomers by the same conventional method, it can be obtained by regenerating the original stereoisomer.

In addition, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds of the invention are not specified otherwise. Cases are included within the scope of the present invention. For example, when X is shown as follows (R ⁴ is hydrogen):

,

,

It is understood that the compounds may also exist in the following tautomeric forms:

또는

or

More specifically, the compound of formula (I) may comprise two or more chiral centers represented by the symbols * and ** in the formula

In one stereoisomer, the carbon atoms identified by the symbols * and ** both have a (R) configuration. This embodiment of the invention is represented by formula Ia:

In this embodiment, the compound is one having a (R, R) configuration at the carbon atoms represented by the symbols * and **, or an enhanced stereoisomeric form having a (R, R) configuration at the carbon atom.

In other embodiments, both carbon atoms represented by the symbols * and ** have a (S) configuration. This embodiment of the invention is represented by formula Ib:

In this embodiment, the compound is one having a (S, S) configuration at the carbon atoms indicated by the symbols * and **, or an enhanced stereoisomeric form having a (S, S) configuration at these carbon atoms.

In another stereoisomer, the carbon atom represented by the symbol * has a (S) configuration and the carbon atom represented by the symbol ** has a (R) configuration. This embodiment of the invention is represented by formula Ic:

In this embodiment, the compound is one having an (S, R) configuration at the carbon atoms indicated by the symbols * and **, or an enhanced stereoisomeric form having (S, R) configuration at such carbon atoms.

In another stereoisomer, the carbon atom represented by the symbol * has a (R) configuration and the carbon atom represented by the symbol ** has a (S) configuration. This embodiment of the invention is shown in formula Id:

In this embodiment, the compound has a (R, S) configuration at the carbon atoms represented by the symbols * and **, or a stereoisomer type having an (R, S) configuration at such carbon atoms.

Compounds of Formulas (Ia) and (Ib) are enantiomers, and therefore, in individual embodiments, the present invention comprises individual enantiomers (ie, Ia or Ib), racemic mixtures of Ia and Ib or predominantly or predominantly Ib, respectively. To an enantiomer-enhanced mixture of Ia and Ib. Similarly, compounds of Formulas (Ic) and (Id) are enantiomers, and therefore, in separate embodiments, the present invention is directed to individual enantiomers (ie, Ic or Id), racemic mixtures of Ic and Id, or predominantly Id, respectively. Predominantly comprising an enantiomer-rich mixture of Ic and Id.

In some embodiments, in order to optimize the therapeutic activity of the compounds of the present invention, for example to treat hypertension, the carbon atoms represented by the symbols * and ** are designated (R, R), (S, S), It may be desirable to have (S, R), or (R, S) coordination or enhanced stereoisomeric forms having such coordination. For example, in one embodiment, a compound of the present invention has a (S, R) configuration of Formula Ic, or is enriched in a stereoisomeric form having a (S, R) configuration, and in another embodiment, The compound has the (R, S) configuration of the formula (Id), or is an enhancement of the stereoisomer type having the (R, S) configuration. In another embodiment, the compounds of the present invention exist as racemic compounds, for example enantiomeric mixtures of formulas Ia and Ib or as enantiomeric mixtures of formulas Ic and Id.

Compounds of the present invention and compounds used for their synthesis may also include compounds labeled with isotopes, i.e. compounds enriched with elements having an atomic weight different from the atomic weight at which one or more elements predominantly found in nature. . Examples of isotopes that may be incorporated into the compounds of formula I include, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ³⁶ Cl, and ¹⁸ F However, the present invention is not limited thereto. Particularly important are compounds of formula I wherein tritium or carbon-14 is enriched, which can be used, for example, in tissue distribution studies; Compounds of formula I fortified with deuterium, especially at the site of metabolism, resulting in compounds with, for example, better metabolic stability; And compounds of formula (I) enhanced with positron emission isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, which can be used, for example, in Positron Emission Topography (PET) studies.

The nomenclature used herein to refer to a compound of the present invention is described in the Examples herein. This nomenclature was derived using commercially available AutoNom software (MDL, San Leandro, Calif.).

representative Example

The substituents and values described below are intended to provide representative examples of various aspects and embodiments of the invention. These representative values are intended to further define and illustrate such aspects and embodiments, and are not intended to exclude other embodiments or to limit the scope of the invention. In this regard, the representation that a particular value or substituent is preferred is not intended to exclude other values or substituents from the present invention in any manner unless specifically indicated.

In one aspect, the invention relates to compounds of formula (I)

R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ . The R ⁷ moiety is selected from:

H;

-C _{1 - 8} alkyl, _{e.g., -CH 3, -CH 2 CH 3} , - (CH 2) 2 CH 3, -CH (CH 3) 2, -CH 2 CH (CH 3) 2, - ( CH ₂ ) ₃ CH ₃ ,-(CH ₂ ) ₄ CH ₃ ,-(CH ₂ ) ₂ CH (CH ₃ ) ₂ ,-(CH ₂ ) ₅ CH ₃ , and-(CH ₂ ) ₆ CH ₃ ;

-C _{1 - 3} alkylene -C _{6 - 10} aryl, e.g., benzyl;

-C _{1 - 3} alkylene -C _{1 - 9} heteroaryl group, e.g., -CH ₂ - pyridinyl, and - (CH _{2) 2} - pyridinyl;

-C _{3 - 7} cycloalkyl, e.g., cyclopentyl;

-[(CH ₂ ) ₂ O] _1-3 CH ₃ , for example-(CH ₂ ) ₂ OCH ₃ and-[(CH ₂ ) ₂ O] ₂ CH ₃ ;

-C _{1 - 6} alkylene group -OC (O) R ^10, for _{example, -CH 2 OC (O) CH} 3, -CH 2 OC (O) CH 2 CH 3, -CH 2 OC (O) (CH ₂ ) ₂ CH ₃ , -CH ₂ CH (CH ₃ ) OC (O) CH ₂ CH ₃ , -CH ₂ OC (O) OCH ₃ , -CH ₂ OC (O) OCH ₂ CH ₃ , -CH (CH ₃ ) OC (O) OCH ₂ CH ₃ , -CH (CH ₃ ) OC (O) O-CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) OC (O) -cyclopentyl, -CH ₂ OC ( O) O-cyclopropyl, -CH (CH ₃ ) -OC (O) -O-cyclohexyl, -CH ₂ OC (O) O-cyclopentyl, -CH ₂ CH (CH ₃ ) OC (O) -phenyl , -CH ₂ OC (O) O-phenyl, -CH ₂ OC (O) -CH [CH (CH ₃ ) ₂ ] -NH ₂ , -CH ₂ OC (O) -CH [CH (CH ₃ ) ₂ ] -NHC (O) OCH ₃ , and -CH (CH ₃ ) OC (O) -CH (NH ₂ ) CH ₂ COOCH ₃ ;

-C _{1 - 6} alkylene -NR ¹² R ^13, _{e.g., - (CH 2) 2 -N} (CH 3) 2,

및

;

And

;

-C _{1 - 6} alkylene -C (O) R ^31, for _{example, -CH 2 C (O) OCH} 3, -CH 2 C (O) O- _{benzyl, -CH 2 C (O) -N} ( CH ₃ ) ₂ , and

;

;

-C _{0 - 6} alkylene-morpholinyl, for example, - (CH _{2) 2} - morpholinyl and - (CH _{2) 3} - morpholinyl:

및

;

And

;

-C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, _{e.g., - (CH 2) 2 SO} 2 CH 3;

, 예를 들어,

;

, E.g,

;

;

;

; 및

; And

.

.

The R ¹⁰ moiety is selected from:

-C _{1 - 6} alkyl, e.g., -CH ₃ and -CH ₂ CH _3;

-OC _{1 - 6} alkyl, for _{example, -OCH 3, -O-CH 2} CH 3, and _{-O-CH (CH 3) 2} ;

-C _{3 - 7} cycloalkyl, e.g., cyclopentyl;

-OC _{3 - 7} cycloalkyl, e.g., cyclopropyl -O-, -O- cyclohexyl, cyclopentyl, and -O-;

Phenyl;

-O-phenyl;

-NR ¹² R ¹³ ;

_{-CH [CH (CH 3) 2} ] -NH 2;

_{-CH [CH (CH 3) 2} ] -NHC (O) OC 1 - 6 alkyl, _{e.g., -CH [CH (CH 3)} 2] -NHC (O) OCH 3; And _{-CH (NH 2) CH 2 COOCH} 3.

R ¹² and R ¹³ moiety is independently H, -C _{1 - 6} alkyl (e.g., CH _3), and is selected from benzyl. Alternatively, the R ¹² and R ¹³ moieties can be, for example,-(CH ₂ ) _3-6- , -C (O)-(CH ₂ ) _3- , or-( CH ₂ ) ₂ O (CH ₂ ) ₂ — may be taken together:

,

, 및

.

,

, And

.

R ³¹ moiety is -OC _{1 - 6} alkyl, for example, -OCH _3, -O- benzyl, and -NR ¹² R ^13, for example, -N (CH _{3) 2,} and

으로부터 선택된다.

.

R ³² moiety is -C _{1 - 6} alkyl (e.g., -CH ₃ and -C (CH _{3) 3)} or -C _{0 - 6} is alkylene -C _{6 -10} aryl.

The R ⁸ moiety is selected from:

H;

-OH;

-OC (O) R ¹⁴ , for example -OC (O) CH ₃ , -OC (O) -phenyl, -OC (O) -OCH ₂ -phenyl, -OC (O) -CH ₂ O-phenyl , -OC (O) (NH ₂ ), and -OC (O) [N (CH ₃ ) ₂ ;

-CH ₂ COOH;

-O-benzyl;

Pyridyl; And

-OC (S) NR ¹⁵ R ¹⁶ , for example -OC (S) NH ₂ and -OC (S) N (CH ₃ ) ₂ .

The R ¹⁴ moiety is selected from:

H;

-C _{1 - 6} alkyl, e.g., -CH _3;

-C _{6 - 10} aryl, e.g., phenyl;

-OCH ₂ -C _{6 - 10} aryl, for example, -OCH ₂ - phenyl;

-CH ₂ OC _{6 - 10} aryl, e.g., -CH ₂ O- phenyl; And

-NR ¹⁵ R ¹⁶ , for example -NH ₂ and N (CH ₃ ) ₂ .

R ¹⁵ and R ¹⁶ moieties is selected from H and -C _{1 independently} is selected from _4-alkyl.

R ⁹ Moiety is H, -C _{1 - 6} alkyl (e.g., -CH _3), and -C (O) R (e.g., -C (O) H) ¹⁷ is a residue selected from. R ¹⁷ moiety is H, -C _{1 - 6} alkyl _{(e.g., -CH 2 CH 3), -C} 3 - 7 cycloalkyl (e.g., cyclopropyl), -C _{6 - 10} aryl (e. g., phenyl), and -C _{1 - 9} is selected from heteroaryl (e.g., pyridine).

In addition, each alkyl group of R ¹ is optionally substituted with 1 to 8 fluorine atoms. For example, if R ¹ is -OR ^7, R ⁷ is -C _{1 - 8} as an alkyl, R ¹ is also _{-OCH (CH 3) CF 3,} -OCH 2 CF 2 CF 3, -OCH (CF 3 ) ₂ , -O (CH ₂ ) ₂ CF ₃ , -OCH (CH ₂ F) ₂ , -OC (CF ₃ ) ₂ CH ₃ , and -OCH (CH ₃ ) CF ₂ CF ₃ .

In one embodiment, R ¹ is selected from -OR ^7, where R ⁷ is H, -C _{1 - 8} alkyl, -C _{1 - 6} alkylene group ^{-OC (O) R 10, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, and

로부터 선택되고,

≪ / RTI >

Wherein R ¹⁰ is -OC _{3 - 7} cycloalkyl; And -NR ⁸ R ⁹ , wherein R ⁸ is H and R ⁹ is H. In other embodiments, such compounds have Formula III.

In one embodiment, R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , wherein R ⁷ is H, R ⁸ is H or —OH, and R ⁹ is H. In other embodiments, such compounds have Formula III.

In another embodiment, R ¹ is -OR ^7, wherein R ⁷ is -C _{1 - 8} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7 cycloalkyl, - [(CH 2) 2} O] 1-3 CH 3, -C 1 - 6 alkylene group ^{-OC (O) R 10, -C} 1 - 6 alkylene -NR ¹² R ^13, -C _{1 - 6} alkylene ^{-C (O) R 31, -C} 0 - 6 alkylene-morpholinyl; -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl;

,

,

, 및

으로부터 선택된다.

,

,

, And

.

In another embodiment, R ¹ is —NR ⁸ R ⁹ ; Wherein R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ⁹ is H. In another embodiment, R ¹ is —NR ⁸ R ⁹ , wherein R ⁸ is H or —OH; R ⁹ is -C _{1 - 6} alkyl, or is -C (O) R ^17. In another embodiment, R ¹ is —NR ⁸ R ⁹ , wherein R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R Selected from ¹⁶ ; R ⁹ is -C _{1 - 6} alkyl, or is -C (O) R ^17. In other embodiments, such compounds have Formula III. In one aspect of the invention, such compounds may find particular utility as prodrugs or as prodrugs or intermediates in the synthetic methods described herein. For example, in one embodiment, R ¹ is -OR ^7, and, R ⁷ is _{-O-CH (CH 3) OC} (O) -O- , such as cyclohexyl, -C _{1 - 6} alkylene group -OC (O R ¹⁰ then:

,R ¹ =

,

Make this compound a cilexetil ester; Or R ¹ is -OR ⁷ and R ⁷ is -O- (CH _{2) 2} - ₀ -C know, such as _{morpholinyl-6} alkylene-morpholinyl then:

R ¹ =

Making this compound as 2-morpholinoethyl or mofetyl ester; Or R ¹ is -OR ⁷ and R ⁷ is -O-CH ₂ -5-methyl- [1,3] dioxol-2-one

이어서:

next:

R ¹ =

This compound is made into medoxomil ester.

R ² is H or -P (O) (OH) ₂ . R ² may also form —CR ¹⁸ R ¹⁹ — with R ⁷ or —C (O) — with R ⁸ . R ¹⁸ and R ¹⁹ are independently selected from H, -C _{1 - 7} can be formed or selected from cycloalkyl, R ¹⁸ and R ¹⁹ together are = O _{- 6} alkyl, and -OC _3. In one embodiment, R ² is H. In other embodiments, such compounds have Formula III.

When R ² forms -CR ¹⁸ R ¹⁹ -with R ⁷ , this embodiment can be shown as follows:

When R ¹⁸ and R ¹⁹ together form ═O, this embodiment may be shown as follows:

When R ² is taken with R ⁸ to form —C (O) — this embodiment may be depicted as follows:

In one aspect of the invention, such compounds may find particular utility as intermediates in prodrugs or the synthetic methods described herein. In other embodiments, such compounds have Formula III. Compounds in which R ² is -P (O) (OH) ₂ may also find utility as prodrugs.

"X" moiety is -C _{1 - 9} heteroaryl, the point of attachment is any available carbon or nitrogen ring atoms. Note that in some embodiments, R ³ and / or R ⁴ may be absent. When R ³ is present, it is on any possible carbon atom. When R ⁴ is present, it is on any possible carbon or nitrogen atom. The heteroaryl ring _9, including the following: By way of illustration and not limitation _- illustratively -C _1:

The pyrazole ring is as follows:

및

,

And

,

Specific examples thereof include:

,

,

, 및

;

,

,

, And

;

Imidazole rings such as:

,

, 및

,

,

, And

,

Specific examples thereof include:

,

,

및

;

,

,

And

;

Triazole rings include 1,2,3-triazole and:

및

,

And

,

Contains 1,2,4-triazoles as follows:

,

및

;

,

And

;

Contains the following benzotriazoles:

,

,

Specific examples thereof include:

,

및

;

,

And

;

Furan Rings:

,

,

Specific examples thereof include:

및

;

And

;

Pyrrole ring:

,

,

Specific examples include:

;

;

Tetrazole as follows:

및

;

And

;

Pyrazine ring:

,

,

Specific examples thereof include:

;

;

Thiophene ring:

,

,

Specific examples thereof include:

및

;

And

;

Oxazole Rings:

,

,

Specific examples thereof include:

,

,

,

및

;

,

,

,

And

;

Isoxazole Rings:

,

,

Specific examples include:

,

,

및

;

,

,

And

;

Thiazole ring:

Specific examples include:

,

,

,

, 및

;

,

,

,

, And

;

Isothiazole Rings:

;

;

Oxadiazole rings have the following [1,2,4] oxadiazoles:

및

,

And

,

And [1,2,3] oxadiazoles as follows:

및

,

And

,

And [1,3,4] oxadiazoles:

;

;

The thiadiazole ring is [1,2,4] thiadiazole as follows:

및

,

And

,

And [1,2,3] thiadiazole, such as:

및

,

And

,

And [1,3,4] thiadiazole:

;

;

Pyridazine ring:

;

;

Pyridine Rings:

,

,

Specific examples include:

,

, 및

;

,

, And

;

Pyrimidine Rings:

,

,

Specific examples include:

,

,

, 및

;

,

,

, And

;

Piran ring

및

;

And

;

Benzimidazole rings as follows:

및

,

And

,

Specific examples include:

,

, 및

;

,

, And

;

Benzoxazole rings as follows:

및

,

And

,

Specific examples include:

및

;

And

;

Benzothiazole rings as follows:

및

,

And

,

Specific examples include:

및

;

And

;

Pyridylimidazole rings as follows:

및

,

And

,

Specific examples include:

; 및

; And

Pyridyltriazole rings as follows:

,

,

, 및

,

,

,

, And

,

Specific examples thereof include:

,

, 및

.

,

, And

.

In one specific embodiment, X is pyrazole, imidazole, triazole, benzotriazole, furan, pyrrole, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, Thiadiazole, pyridazine, pyridine, pyrimidine, pyran, benzimidazole, benzoxazole, benzothiazole, pyridylimidazole, and pyridyltriazole.

Some -C _{1 - 9} heteroaryl ring may be present in tautomeric form, and such tautomeric form is a part of the present invention, it is understood to be encompassed by the term "heteroaryl (heteroaryl)". Accordingly, the compound is a -C _{1 -} If depicted as having a ₉ heteroaryl ring, the compounds also may be present in tautomeric form, and vice versa, and that, it is understood that both forms included in the invention.

-C _{1 - 9} heteroaryl ring Exemplary rings Exemplary Tautomer (s) Pyrazole

Imidazole

Triazole

Oxazole

Thiazole

Isothiazole

Oxadiazole

Thiadiazole

Pyridazine

In one specific embodiment, X is pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benz Oxazole, pyridylimidazole, and pyridyltriazole. In other embodiments, X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole. In another embodiment, X is isoxazole, and in one particular embodiment has the formula III:

Wherein R ¹ -R ⁶ , a, and b are as defined for Formula (I). In another embodiment, compounds of the present invention have formula IIIa:

Wherein R ¹ , R ⁵ , R ⁶ , a, and b are as defined for Formula (I). In another embodiment, compounds of the present invention have formula IIIb:

Wherein R ¹ , R ⁵ , R ⁶ , a, and b are as defined for Formula (I).

The R ³ residue may be absent. When present, R ³ is attached to a carbon atom of the "X" group and is selected from:

H;

Halo such as chloro and fluoro;

-C _{0 - 5} alkylene group -OH, for _{example, -OH, -CH 2 OH, -CH} (OH) CH 3, and -C (CH _{3) 2} -OH;

-NH ₂ ;

-C _{1 - 6} alkyl, _{e.g., -CH 3, - (CH 2} ) 2 CH 3, -CH (CH 3) 2, and _{- (CH 2) 3 -CH 3} ;

-CF _3;

-C _{3 - 7} cycloalkyl, e.g., cyclopropyl and cyclohexyl;

-C _{0 - 2} alkylene -OC _{1 - 6} alkyl, for _{example, -OCH 3, -OCH 2 CH 3} , -CH 2 -OCH 3, and _{- (CH 2) 2 -OCH 3} ;

-C (O) R ²⁰ , for example -C (O) H and -C (O) CH ₃ ;

-C _{0 - 1} alkylene -COOR ^21, for _{example, -COOH, -CH 2 -COOH, -C} (O) OCH 2 CH 3, -C (O) O- (CH 2) 2 OCH 3 -C (O) O-CH ₂ OC (O) CH ₃ , -CH ₂ -C (O) O-CH ₂ OC (O) CH ₃ , -C (O) O-CH ₂ OC (O) O- CH ₃ , -CH ₂ -C (O) O-CH ₂ OC (O) O-CH ₃ , -C (O) O-CH (CH ₃ ) OC (O) O-CH ₂ CH ₃ , -C ( O) O-CH (CH ₃ ) OC (O) O-CH (CH ₃ ) ₂ , -C (O) O-CH ₂ CH (CH ₃ ) OC (O) -cyclopentyl, -C (O) O -CH ₂ OC (O) O-cyclopropyl, -C (O) O-CH (CH ₃ ) -OC (O) -O-cyclohexyl, -C (O) O-CH ₂ OC (O) O- Cyclopentyl, -C (O) O-CH ₂ CH (CH ₃ ) OC (O) -phenyl, -C (O) O-CH ₂ OC (O) O-phenyl, -C (O) O-CH ₂ -Pyridine, -C (O) O-CH ₂ -pyrrolidine, -C (O) O- (CH ₂ ) ₂ -morpholinyl, -C (O) O- (CH ₂ ) ₃ -morpholinyl , And -C (O) O- (CH ₂ ) ₂ -SO ₂ -CH ₃ ;

-C (O) NR ²² R ²³ , for example -C (O) NH ₂ , -C (O) NHCH ₃ , -C (O) N (CH ₃ ) ₂ , -C (O) NH- ( CH ₂ ) ₂ CH ₃ , -C (O) NH-CH ₂ COOH, -C (O) NH- (CH ₂ ) ₂ -OH, -C (O) NH- (CH ₂ ) ₂ -N (CH ₃ ) ₂ , -C (O) NH-cyclopropyl, -C (O) NH- (CH ₂ ) ₂ -imidazolyl, -C (O) N (CH ₃ ) -CH ₂ CH (CH ₃ ) ₂ , And -C (O) N (CH ₃ ) [(CH ₂ ) ₂ OCH ₃ ];

-NHC (O) R ²⁴ , for example -NHC (O) -CH ₂ CH ₃ , -NHC (O)-(CH ₂ ) ₃ CH ₃ , -NHC (O) O-CH ₂ CH ₃ ,- NHC (O) —CH ₂ —OCH ₃ , —NHC (O) -2-methoxyphenyl, —NHC (O) -2-chlorophenyl, and —NHC (O) -2-pyridine;

= O;

-NO ₂ ;

-C (CH ₃ ) = N (OH);

Phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl (eg, phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-NHC (O) CH ₃ -Phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-biphenyl, 2,5-dichlorophenyl, 2,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2-meth Oxy, 5-fluorophenyl, and 3,4-dichlorophenyl);

Naphthalenyl;

Pyridinyl;

Pyrazinyl;

Pyrazolyl optionally substituted with methyl;

Thiophenyl optionally substituted with methyl or halo (eg chloro);

Furanyl; And

-CH ₂ -morpholinyl.

R ²⁰ moieties are H and -C _{1 - 6} is selected from alkyl (e.g., -CH _3). The R ²¹ moiety is selected from:

H;

-C _{1 - 6} alkyl, e.g., -CH ₃ and -CH ₂ CH _3;

-C _{1 - 3} alkylene -C _{6 - 10} aryl;

-C _{1 - 3} alkylene -C _{1 - 9} for a heteroaryl group, for example, -CH ₂ - pyridine;

-C _{3 - 7} cycloalkyl;

-[(CH ₂ ) ₂ O] _1-3 CH ₃ , for example-(CH ₂ ) ₂ OCH ₃ ;

-C _{1 - 6} alkylene group -OC (O) R ^25, for _{example, -CH 2 OC (O) CH} 3, -CH 2 OC (O) O-CH 3, -CH 2 OC (O) O- CH ₃ , -CH (CH ₃ ) OC (O) O-CH ₂ CH ₃ , -CH (CH ₃ ) OC (O) O-CH (CH ₃ ) _2, -CH ₂ CH (CH ₃ ) OC (O ) -Cyclopentyl, -CH ₂ OC (O) O-cyclopropyl, -CH (CH ₃ ) -OC (O) -O-cyclohexyl, -CH ₂ OC (O) O-cyclopentyl, -CH ₂ CH (CH ₃ ) OC (O) -phenyl, and -CH ₂ OC (O) O-phenyl;

-C _{1 - 6} alkylene -NR ²⁷ R ^28, for example, -CH ₂ - pyrrolidine;

-C _{1 - 6} alkylene -C (O) R ^33;

-C _{0 - 6} alkylene-morpholinyl, for example, - (CH _{2) 2} - morpholinyl and - (CH _{2) 3} - morpholinyl:

및

;

And

;

-C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, _{e.g., - (CH 2) 2 -SO} 2 -CH 3;

, 예를 들어,

;

, E.g,

;

;

;

;

;

; 및

; And

.

.

R ²² and R ²³ residues are independently selected from:

H;

-C _{1 - 6} alkyl, e.g., -CH ₃ and _{- (CH 2) 2 CH 3} ;

-CH ₂ COOH;

-(CH ₂ ) ₂ OH;

-(CH ₂ ) ₂ OCH ₃ ;

-(CH ₂ ) ₂ SO ₂ NH ₂ ;

-(CH ₂ ) ₂ N (CH ₃ ) ₂ ;

-C _{0 - 1} alkylene -C _{3 - 7} cycloalkyl, e.g., cyclopropyl, and -CH ₂ - cyclopropyl; And

-(CH ₂ ) ₂ -imidazolyl.

R ²² and R ²³ are taken together also halo, -OH, -COOH, or is optionally substituted with -CONH _2, optionally, a saturated or partially unsaturated ring containing an oxygen atom in the -C _{3 - 5} a heterocycle Can be formed. Saturated -C _{3 -} to ₅ heterocycles include azetidine, pyrrolidine, piperidine and morpholine, and includes an exemplary R ³ group, and then:

,

,

,

,

,

,

, 및

.

,

,

,

,

,

,

, And

.

A partially unsaturated -C _{3 -} to ₅ heterocycles include 2,5-dihydro -1H- pyrrole, it comprises an exemplary R ³ group, and then:

.

.

The R ²⁴ moiety is selected from:

-C _{1 - 6} alkyl, e.g., -CH ₂ CH ₃ and _{- (CH 2) 3 CH 3} ;

-C _{0 - 1} alkylene -OC _{1 - 6} alkyl, e.g., -O-CH ₂ CH ₃ and -CH ₂ -OCH _3;

Phenyl optionally substituted with halo or -OCH ₃ , for example -2-chlorophenyl or -2-methoxyphenyl; And

-C _{1 - 9} heteroaryl group, e.g., 2-pyridine.

R ²⁵ is selected from:

-C _{1 - 6} alkyl, _{e.g., -CH 3, -CH 2 CH 3} , and _{- (CH 2) 3 CH 3} ;

-OC _{1 - 6} alkyl, for _{example, -OCH 3, -OCH 2 CH 3} , and -OCH (CH _{3) 2;}

-C _{3 - 7} cycloalkyl, e.g., cyclopentyl;

-OC _{3 - 7} cycloalkyl, e.g., cyclopropyl -O-, -O- cyclopentyl, cyclohexyl, and -O-;

Phenyl;

-O-phenyl;

-NR ²⁷ R ²⁸ ;

_{-CH [CH (CH 3) 2} ] -NH 2;

_{-CH [CH (CH 3) 2} ] -NHC (O) OC 1 - 6 alkyl, _{e.g., -CH [CH (CH 3)} 2] -NHC (O) OCH 3; And

-CH (NH ₂ ) CH ₂ COOCH ₃ .

R ²⁷ and R ²⁸ are independently selected from H, -C _{1 - 6} alkyl, and being selected from benzyl, or R ²⁷ and R ²⁸ are taken together _{- (CH 2) 3-6 -,} -C (O) - (CH ₂ ) _3- , or-(CH ₂ ) ₂ O (CH ₂ ) _2- ; R ³³ is -OC _{1 - 6} alkyl, -O- benzyl, and is selected from -NR ²⁷ R ^28; R ³⁴ is -C _{1 - 6} alkyl (e.g., -CH ₃ and -C (CH _{3) 3)} or -C _{0 -} a _{10-aryl-6-alkylene} -C _6.

In addition, each alkyl group of R ³ is optionally substituted with 1 to 8 fluorine atoms. For example, R ³ is -C _{0 - 1} is alkylene -COOR ^21, R ²¹ is -C _{1 - 6} when the alkyl, R ³ is also _{-COOCH (CH 3) CF 3,} -COOCH 2 CF 2 CF ₃ , -COOCH (CF ₃ ) ₂ , -COO (CH ₂ ) ₂ CF ₃ , -COOCH (CH ₂ F) ₂ , -COOC (CF ₃ ) ₂ CH ₃ , and -COOCH (CH ₃ ) CF ₂ CF ₃ Wow It can be the same.

In one embodiment, R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl substituted with methyl; Thiophenyl substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl; R ²⁰ is -C _{1 - 6} alkyl; R ²¹ is selected from H and -C _{1 - 6} alkyl is selected from; R ²² is selected from H and -C _{1 - 6} alkyl is selected from; R ²³ is H, -C _{1 - 6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH, - (CH 2) 2 OCH 3, - (CH 2) 2 N (CH 3) 2, -C 3 _{- 7} cycloalkyl, and - (CH _{2) 2} -, or already selected from thiazolyl; Or R ²² and R ²³ taken together are optionally substituted with —OH or —CONH ₂ , Forms azetidine, pyrrolidine, piperidine or morpholine; R ²⁴ is -C _{1 - 6} alkyl; -C _{0 - 1} alkylene -OC _{1 - 6} alkyl; Phenyl substituted with halo or -OCH ₃ ; And pyridine. In other embodiments, such compounds have Formula III.

In one embodiment, R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -NO ₂ ; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl optionally substituted with methyl; Thiophenyl optionally substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl, R ²¹ is H. In other embodiments, such compounds have Formula III.

In another embodiment, R ³ is -C _{0 - 1} is alkylene -COOR ^21, R ²¹ is -C _{1 - 6} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkyl, alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7 cycloalkyl, - [(CH 2) 2} O] 1-3 CH 3, -C 1 - 6 alkylene group -OC (O) R ^25; -C _{1 - 6} alkylene _{^{-NR 27 R 28, -C 1 -}} 6 alkylene ^{-C (O) R 33, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ - C _{1 - 6} alkyl,

;

,

, 및

로부터 선택된다.

;

,

, And

.

In one aspect of the invention, such compounds may find particular utility as intermediates in prodrugs or the synthetic methods described herein.

The R ⁴ moiety may be absent. When present, R ⁴ is attached to a carbon or nitrogen atom of the "X" group and is selected from:

H;

-OH;

-C _{1 - 6} alkyl, e.g., -CH _3;

-C _{1 - 2} alkylene group -COOR ^35, for example, -CH ₂ COOH and - (CH _{2) 2} -COOH;

—CH ₂ OC (O) CH (R ³⁶ ) NH ₂ , eg, —CH ₂ OC (O) CH [CH (CH ₃ ) ₂ ] NH ₂ ;

—OCH ₂ OC (O) CH (R ³⁶ ) NH ₂ , eg, —OCH ₂ OC (O) CH [CH (CH ₃ ) ₂ ] NH ₂ ;

-OCH ₂ OC (O) CH ₃ ;

-CH ₂ OP (O) (OH) ₂ ;

-CH ₂ CH (OH) CH ₂ OH;

_{-CH [CH (CH 3) 2} ] -NHC (O) OC 1 - 6 alkyl;

Pyridinyl; And

Phenyl or benzyl (eg, 4-chlorophenyl, 3-methoxyphenyl, 2,4- optionally substituted with one or more groups selected from halo, -COOR ³⁵ , -OCH ₃ , -OCF ₃ , and -SCF ₃₎ Dichlorophenyl, 3,4-dichlorophenyl, 2-chloro, 5-fluorophenyl, 3-trifluoromethoxy, 4-chlorophenyl, 3-trifluoromethylsulfanyl, 4-chlorophenyl, 2,6- Difluoro, 4-chlorophenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-carboxybenzyl, 4-carboxybenzyl, 3-methoxybenzyl, 2-chloro, 5-fluorobenzyl, 3-chloro, 5-fluorobenzyl, 2-fluoro, 4-chlorobenzyl, 3-chloro, 4-fluorobenzyl, 3-OCF3, 4-chlorobenzyl, 3-SCF3, 4-chlorobenzyl, 2, 6-difluoro, 3-chlorobenzyl, 2,6-difluoro, 4-chlorobenzyl, and 2,3,5,6-tetrafluoro, 4-methoxy benzyl).

The R ³⁵ moiety is selected from:

H;

-C _{1 - 6} alkyl, e.g., -CH ₃ and -CH ₂ CH _3;

-C _{1 - 3} alkylene -C _{6 - 10} aryl;

-C _{1 - 3} alkylene -C _{1 - 9} for a heteroaryl group, for example, -CH ₂ - pyridine;

-C _{3 - 7} cycloalkyl;

-[(CH ₂ ) ₂ O] _1-3 CH ₃ , for example-(CH ₂ ) ₂ OCH ₃ ;

-C _{1 - 6} alkylene group -OC (O) R ^25, for _{example, -CH 2 OC (O) CH} 3, -CH 2 OC (O) O-CH 3, -CH 2 OC (O) O- CH ₃ , -CH (CH ₃ ) OC (O) O-CH ₂ CH ₃ , -CH (CH ₃ ) OC (O) O-CH (CH ₃ ) _2, -CH ₂ CH (CH ₃ ) OC (O ) -Cyclopentyl, -CH ₂ OC (O) O-cyclopropyl, -CH (CH ₃ ) -OC (O) -O-cyclohexyl, -CH ₂ OC (O) O-cyclopentyl, -CH ₂ CH (CH ₃ ) OC (O) -phenyl, and -CH ₂ OC (O) O-phenyl;

-C _{1 - 6} alkylene -NR ²⁷ R ^28, for example, -CH ₂ - pyrrolidine;

-C _{1 - 6} alkylene -C (O) R ^33;

-C _{0 - 6} alkylene-morpholinyl, for example, - (CH _{2) 2} - morpholinyl and - (CH _{2) 3} - morpholinyl:

및

;

And

;

-C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, _{e.g., - (CH 2) 2 -SO} 2 -CH 3;

, 예를 들어,

;

, E.g,

;

;

;

; 및

; And

.

.

R ²⁵ , R ²⁷ , R ²⁸ , R ³³ , and R ³⁴ moieties are as defined above. R ³⁶ moiety is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl.

In addition, each alkyl group of R ⁴ is optionally substituted with 1 to 8 fluorine atoms. For example, R ⁴ is -C _{1 - 2} alkylene -COOR ^35, R ³⁵ is -C _{1 - 6} alkyl, and, R ⁴ is also _{-COOCH (CH 3) CF 3,} -COOCH 2 CF 2 CF 3 , -COOCH (CF ₃ ) ₂ , -COO (CH ₂ ) ₂ CF ₃ , -COOCH (CH ₂ F) ₂ , -COOC (CF ₃ ) ₂ CH ₃ , and -COOCH (CH ₃ ) CF ₂ CF ₃ It can be the same.

The R ⁴ moiety can also be taken with R ³ to form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- . For illustrative purposes only, this embodiment is shown below as X is pyrazole. It is understood that other X groups can also be used.

,

,

,

,

,

,

, 및

, And

In other specific embodiments, R ⁴ is absent or H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; Phenyl optionally substituted with one halo group; And benzyl optionally substituted with one or more groups selected from halo, -COOH, -OCH ₃ , -OCF ₃ , and -SCF ₃ ; R ³⁵ is H; R ³⁶ is —CH (CH ₃ ) ₂ ; Or R ³ and R ⁴ are taken together to form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- . In other embodiments, such compounds have Formula III.

In one embodiment, R ⁴ is absent or H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; -CH ₂ OC (O) CH (R ³⁶ ) NH ₂ , -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; And phenyl or benzyl optionally substituted with one or more groups selected from halo, -COOR ³⁵ , -OCH ₃ , -OCF ₃ , and -SCF ₃ ; R ³⁵ is H. In other embodiments, such compounds have Formula III.

In other embodiments, R ⁴ is —OCH ₂ OC (O) CH ₃ ; -CH ₂ OP (O) (OH) ₂ ; -C _{1 - 2} alkylene -COOR ^35; And phenyl or benzyl substituted with one or more -COOR ³⁵ groups; Wherein R ³⁵ is -C _{1 - 6} alkyl, -C _1-3 alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - [ _{(CH 2) 2 O] 1-3} CH 3, -C 1 - 6 alkylene group -OC (O) R ^25; -C _{1 - 6} alkylene _{^{-NR 27 R 28, -C 1 -}} 6 alkylene ^{-C (O) R 33, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ - C _{1 - 6} alkyl,

;

,

, 및

로부터 선택된다.

;

,

, And

.

In one aspect of the invention, such compounds may find particular utility as intermediates in prodrugs or the synthetic methods described herein. In other embodiments such compounds have Formula III.

The numbering for the R ⁵ and R ⁶ groups is as follows:

The integer "a" is 0 or 1. If an R ⁵ moiety is present, it is selected from halo, -CH ₃ , -CF ₃ , and -CN. In one embodiment, a is zero. In other embodiments, a is 1 and R ⁵ is halo, such as 3-chloro or 3-fluoro. The integer "b" is zero or an integer of 1 to 3. When present, the R ⁶ moiety is independently selected from halo, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ . In one embodiment, b is zero. In other embodiments, b is 1 and R ⁶ is selected from Cl, F, -OH, -CH ₃ , -OCH ₃ , and -CF ₃ , for example 2'-chloro, 3'-chloro, 2'-fluoro, 3'-fluoro, 2'-hydroxy, 3'-hydroxy, 3'-methyl, 2'-methoxy, or 3'-trifluoromethyl. In other embodiments, b is 1 and R ⁶ is halo, —CH ₃ , or —OCH ₃ , for example 3′-chloro, 3′-methyl, or 2′-methoxy. In one embodiment, b is 2 and R ⁶ Silver 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2', 5'-difluoro, 2'-methyl-5'-chloro, 3'-fluoro-5'-chloro , 3'-hydroxy-5'-chloro, 3 ', 5'-dichloro, 3', 5'-difluoro, 2'-methoxy-5'-chloro, 2'-methoxy-5'- Fluoro, 2'-hydroxy-5'-fluoro, 2'-fluoro-3'-chloro, 2'-hydroxy-5'-chloro, or 2'-hydroxy-3'-chloro; In other embodiments, b is 2 and each R ⁶ is independently halo, eg, 2'-fluoro-5'-chloro and 2 ', 5'-dichloro. In other embodiments, b is 3 and each R ⁶ is independently halo or -CH ₃ , for example 2'-methyl-3 ', 5'-dichloro or 2'-fluoro-3'-methyl -5'-chloro. In another embodiment a is 1, b is 1 and R ⁵ and R ⁶ are independently halo, eg, 3-chloro and 3′chloro. In other embodiments, such compounds have Formula III. Of particular interest are compounds of the formula:

,

,및

,

, And

Methylene linking group on the biphenyl is one or two -C _{1 - 6} alkyl group or is optionally substituted by cyclopropyl. For example, in one embodiment, the methylene linker on biphenyl is unsubstituted; In other embodiments, the methylene linking group on the biphenyl is substituted by one of the -C _{1 -6} alkyl group (e.g., -CH _3); Further methylene linking group on the biphenyl] In another embodiment the two -C _{1 -} (for example, two -CH ₃ group), ₆ alkyl group which is substituted by; In another embodiment the methylene linking group on biphenyl is substituted with a cyclopropyl group. Each such embodiment is shown as follows:

,

,

, 및

,

,

, And

In another embodiment, R ⁷ is H, -C _{1 - 8} alkyl, -C _{1 - 6} alkylene group ^{-OC (O) R 10, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, and

로부터 선택되고;

≪ / RTI >

R ¹⁰ is -OC _{3 - 7} cycloalkyl; R ⁸ is H; R ⁹ is H; R ² is H; R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl substituted with methyl; Thiophenyl substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl; R ²⁰ is -C _{1 - 6} alkyl; R ²¹ is H or -C _{1 - 6} alkyl, and; R ²² is H or -C _{1 - 6} alkyl; R ²³ is H, -C _{1 - 6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH, - (CH 2) 2 OCH 3, - (CH 2) 2 N (CH 3) 2, -C 3 _{- 7} cycloalkyl, and - (CH _{2) 2} -, or already selected from thiazolyl; Or R ²² and R ²³ taken together form azetidine, pyrrolidine, piperidine or morpholine, optionally substituted with —OH or —CONH ₂ ; R ²⁴ is -C _{1 - 6} alkyl; -C _{0 - 1} alkylene -OC _{1 - 6} alkyl; Phenyl substituted with halo or -OCH ₃ ; And pyridinyl; R ⁴ is absent or H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; Phenyl optionally substituted with one halo group; And benzyl optionally substituted with one or more groups selected from halo, -COOH, -OCH ₃ , -OCF ₃ , and -SCF ₃ ; R ³⁵ is H; R ³⁶ is —CH (CH ₃ ) ₂ ; Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- ; a is 0; Or a is 1 and R ⁵ is 3-chloro; b is 0; Or b is 1 and R ⁶ is 3'-chloro, 3'-methyl, or 2'-methoxy; Or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy; The methylene linkage on biphenyl is optionally substituted with two methyl groups. In one embodiment, X is pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxa Sol, pyridylimidazole, and pyridyltriazole.

In another embodiment, R ¹ is -OR ⁷ ; R ² is H; X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole; R ³ is H; Halo; -C _{0 - 5} alkylene -OH; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, and -OCH ₃ ; Pyridinyl; Pyrazinyl; And thiophenyl substituted with methyl or halo; R ⁴ is H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; And phenyl optionally substituted with one halo group; Or R ³ and R ⁴ are taken together to form -phenylene-O- (CH ₂ ) _1-3- ; a is 0; Or a is 1 and R ⁵ is 3-chloro; b is 0; Or b is 1 and R ⁶ is 3'-chloro, 3'-methyl, or 2'-methoxy; Or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy; R ²⁰ is -C _{1 - 6} alkyl; R ²¹ is H; R ²² is selected from H and -C _{1 - 6} alkyl is selected from; R ²³ is -C _{1 - 6 alkyl, - (CH 2) 2 OCH} 3, and -C _{3 - 7} cycloalkyl or selected from; Or R ²² and R ²³ are taken together to form azetidine, pyrrolidine, or piperidine, optionally substituted with —OH or —CONH ₂ ; R ²⁴ halo or phenyl substituted with -OCH ₃ ; R ³⁵ is H; The methylene linkage on biphenyl is optionally substituted with two methyl groups; R ⁷ is as defined for Formula (I).

A specific group of compounds of Formula I is disclosed in US Provisional Application No. 61 / 423,180, filed December 15, 2010. This group includes a compound of formula (II): or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is selected from -OR ⁷ and -NR ⁸ R ⁹ ; R ⁷ is H; -C _{1 - 6} alkyl; -C _{1 - 3} alkylene -C _{6 - 10} aryl; -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl; -C _{3 - 7} cycloalkyl; -(CH ₂ ) ₂ OCH ₃ ; -C _{1 - 6} alkylene group -OC (O) R ^10; -CH ₂ -pyridine; -CH ₂ -pyrrolidine; -C _{0 - 6} alkylene morpholine; -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl;

;

; 및

로부터 선택되고;

;

; And

≪ / RTI >

Expression in R ¹⁰ is -C _{1 - 6} alkyl, -OC _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -OC _{3 - 7} cycloalkyl, phenyl, -O- phenyl, -NR ¹² R ^13, and - CH (NH ₂ ) CH ₂ COOCH ₃ ; R ¹² and R ¹³ are independently H, -C _{1 - 6} alkyl to form, and being selected from benzyl, or R ¹² and R ¹³ are taken together - - _3-6 (CH _2); R ⁸ is H; -OH; -OC (O) R ¹⁴ ; -CH ₂ COOH; -O-benzyl; Pyridyl; And -OC (S) NR ¹⁵ R ¹⁶ ; Wherein R ¹⁴ is H, -C ₁₆ alkyl, -C _{6 - 10} aryl, -OCH ₂ -C _{6 - 10} aryl, -CH ₂ OC _{6 - 10} aryl, and is selected from -NR ¹⁵ R ^16; R ¹⁵ and R ¹⁶ are independently selected from H and -C _{1 -} is selected from _4-alkyl; R ⁹ is H; -C _{1 - 6} alkyl; And -C (O) R ¹⁷ ; Wherein R ¹⁷ is H; -C _{1 -6} alkyl; -C _{3 - 7} cycloalkyl; -C _{6 - 10} aryl; And -C _{1 - 9} is selected from heteroaryl; R ² is H or taken together with R ¹ to form —OCHR ¹⁸ R ¹⁹ — or —NHC (O) —; R ¹⁸ and R ¹⁹ are independently selected from H, -C _{1 - 6} alkyl, and -OC _{3 - 7,} or selected from a cycloalkyl, or R ¹⁸ and R ¹⁹ Are taken together to form = 0; X is -C _{1 - 5,} and _{heterocyclyl-heteroaryl} or partially unsaturated ₉ -C _3; R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 -6} alkyl; -C _{3 - 7} cycloalkyl; -C _0-1 alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -C (O) OR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; Phenyl optionally substituted with one group selected from halo, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthyl; Pyridine; Pyrazine; Pyrazole optionally substituted with methyl; Thiophene optionally substituted with methyl; And furan; When R ³ is present it is attached to a carbon atom; R ²⁰ is selected from H and -C _{1 - 6} alkyl is selected from; R ²¹ is H; -C _{1 - 6} alkyl; -C _{1 - 3} alkylene -C _{6 - 10} aryl; -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl; -C _{3 - 7} cycloalkyl; -(CH ₂ ) ₂ OCH ₃ ; -C _{1 - 6} alkylene group -OC (O) R ^25; -CH ₂ -pyridine; -CH ₂ -pyrrolidine; -C _{0 - 6} alkylene morpholine; -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl;

;

;및

로부터 선택되고;

;

; And

≪ / RTI >

Wherein R ²⁵ is -C _{1 - 6} alkyl, -OC _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -OC _{3 - 7} cycloalkyl, phenyl, -O- phenyl, -NR ²⁷ R ^28, and -CH (NH ₂ ) CH ₂ COOCH ₃ ; R ²⁷ and R ²⁸ are independently selected from H, -C _{1 - 6} selected from alkyl, and benzyl, or, or R ²⁷ and R ²⁸ are taken together, - to form a - (CH _{2) 3-6;} R ²² and R ²³ are independently H; -C _{1 - 6} alkyl; -CH ₂ COOH; -(CH ₂ ) ₂ OH; -(CH ₂ ) ₂ OCH ₃ ; -(CH ₂ ) ₂ SO ₂ NH ₂ ; -(CH ₂ ) ₂ N (CH ₃ ) ₂ ; -C _{3 - 7} cycloalkyl; And-(CH ₂ ) ₂ -imidazole; Or R ²² and R ²³ are taken together, is optionally substituted with -OH, -COOH, or -CONH _2, optionally containing an oxygen atom in the ring, saturated or partially unsaturated, the -C _{3 -} form a heterocyclic ₅ and; R ²⁴ is -C _{1 - 6} alkyl; -OC _{1 - 6} alkyl; -CH ₂ -OC _{1 - 6} alkyl; Phenyl substituted with -OCH ₃ ; And pyridine; R ⁴ is H; -C _{1 - 6} alkyl; Is selected from halo, -COOH, -OCH ₃ , -OCF ₃ , and phenyl or benzyl substituted with one or more groups selected from -SCF ₃ ; R ⁴ is attached to a carbon or nitrogen atom; a is 0 or 1; R ⁵ is halo or -CF ₃ ; b is 0 or 1; R ⁶ is halo.

In addition, certain interesting compounds of the present invention include the compounds shown in the Examples below and pharmaceutically acceptable salts thereof.

General synthesis method

The compounds of the present invention can be prepared from readily available starting materials or using other methods, reagents, and starting materials known to those skilled in the art, using the methods described in the general methods, examples described below . Although the methods described below describe particular embodiments of the present invention, other embodiments of the present invention may be similarly prepared using the same or similar methods, or employ other methods, reagents and starting materials known to those skilled in the art. It should be understood that it can be prepared by. In addition, it will be understood that other process conditions may also be used unless otherwise specified, given general or preferred process conditions (eg, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.). In some cases, the reaction was performed at room temperature and no substantial temperature measurements were made. Room temperature is understood to mean a temperature within a range generally associated with room temperature in a laboratory environment and is generally understood to be in the range of about 18 ° C to about 30 ° C. In other cases, the reaction was carried out at room temperature and the temperature was actually measured and recorded. Optimum reaction conditions will generally vary depending upon the various reaction parameters, such as the particular reactants, solvent, and amount used, but those skilled in the art will readily be able to determine appropriate reaction conditions using conventional optimization procedures.

In addition, as will be apparent to one skilled in the art, conventional protecting groups may be necessary or desirable to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for particular functional groups and the selection of suitable conditions and reagents for the protection and deprotection of such functional groups are well known in the art. If desired, protecting groups other than those illustrated in the methods described herein can be used. For example, a number of protecting groups, and their introduction and removal, are disclosed in TW Greene and GM Wuts, Protecting Groups in Organic Synthesis, Fourth Edition, Wiley, New York, 2006, and references cited therein .

Carboxy-protecting groups are suitable for preventing undesired reactions at the carboxy group, examples of which include methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl But are not limited to, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), benzhydryl (DPM), and the like. Amino-protecting groups are suitable for preventing unwanted reactions in amino groups, examples being t -butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxy Carbonyl (Fmoc), formyl, trimethylsilyl (TMS), t -butyldimethylsilyl (TBDMS) and the like. A hydroxyl-protecting group suitable for preventing undesirable reactions at a hydroxyl group, and, examples of C _{1 - 6} alkyl, trimethylsilyl (TMS), triethylsilyl (TES), and tert-butyldimethylsilyl (TBDMS a silyl group containing ₆ alkylsilyl groups _-) and C ₁ tree like; ₆ alkanoyl group and an aromatic acyl group (an acyl group) to an ester containing a group such as _benzoyl-, formyl, acetyl, and pivaloyl (pivaloyl) C _1, such as; Arylmethyl groups such as benzyl (Bn), p -methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); And the like, and the like.

Standard deprotection techniques and reagents are used to remove protecting groups and may vary depending on which group is used. For example, sodium or lithium hydroxide is usually used when the carboxy-protecting group is methyl, acids such as TFA or HCl are usually used when the carboxy-protecting group is ethyl or t -butyl, and H ₂ / Pd / C is carboxy- It can be used when the protecting group is benzyl. The BOC amino-protecting group can be removed using an acidic reagent such as TFA in DCM or HCl in 1,4-dioxane, while the Cbz amino-protecting group is H ₂ (1 atm) and 10% Pd / C in alcoholic solvent ( May be removed by employing catalytic hydrogenation conditions such as "H ₂ / Pd / C"). H ₂ / Pd / C is usually used when the hydroxyl-protecting group is benzyl, while NaOH is usually used when the hydroxyl-protecting group is an acyl group.

Suitable bases for use in this scheme are, by way of example and not limitation, potassium carbonate, calcium carbonate, sodium carbonate, triethylamine, pyridine, 1,8-diazabicyclo- [5.4.0] undec-7 -Ene (DBU), N, N -diisopropylethylamine (DIPEA), 4-methylmorpholine, sodium hydroxide, potassium hydroxide, potassium t -butoxide, and metal hydrides.

Suitable inert diluents or solvents for use in this mode are, by way of non-limiting example, tetrahydrofuran (THF), acetonitrile (MeCN), N, N -dimethylformamide (DMF), N, N -dimethylacet Amide (DMA), dimethyl sulfoxide (DMSO), toluene, dichloromethane (DCM), chloroform (CHCl ₃ ), carbon tetrachloride (CCl ₄ ), 1,4-dioxane, methanol, ethanol, water and the like. .

Suitable carboxylic acid / amine coupling reagents are benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N, N, N ' , N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodii include-ethylcarbodiimide (EDCI), carbonyldiimidazole (CDI), 1- hydroxybenzotriazole (HOBt), etc.-imide (DCC), N - (3- dimethylaminopropyl) - N '. The coupling reaction is carried out in an inert diluent in the presence of a base such as DIPEA and is carried out under conventional amide bond-forming conditions.

All reactions are generally carried out at temperatures in the range of about -78 ° C to about 100 ° C, for example at room temperature. The reaction can be monitored until termination using thin layer chromatography (TLC), high performance liquid chromatography (HPLC), and / or LCMS. The reaction may be terminated in minutes or may take several hours, typically 1-2 hours to 48 hours. After termination, the resulting mixture or reaction product may be further processed to obtain the desired product. For example, the resulting mixture or reaction product may be subjected to one or more of the following processes: concentration or partitioning (eg, between EtOAc and water, or between 5% THF and 1M phosphoric acid in EtOAc); Extraction (eg, extraction with EtOAc, CHCl ₃ , DCM, chloroform); Washing (e.g. saturated aqueous NaCl solution, saturated NaHCO ₃ Aqueous solution, Na ₂ CO ₃ (5%), CHCl ₃ Or washing with 1M NaOH); Drying (eg over MgSO ₄ , over Na ₂ SO ₄ , or in vacuo); Filtering; Crystallizing (eg, crystallization from EtOAc and hexanes); Being concentrated (eg in vacuum); And / or purification (eg, silica gel chromatography, flash chromatography, preparative HPLC, reverse phase-HPLC, or crystallization).

The compounds of formula (I) and their salts can be prepared as shown in scheme I below:

system( Scheme ) I

This process includes coupling Compound 1 with Compound 2, wherein R ¹ -R ⁶ , X, a, and b are as defined for Formula I and P ¹ is H or a suitable amino-protecting group Examples include t -butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t -butyldimethylsilyl. When P ¹ is an amino protecting group, the process further comprises the step of deprotecting the compound of formula 1 before or simultaneously with the coupling step.

In examples where R ¹ is such as -OCH ₃ or -OCH ₂ CH ₃ , the coupling step can lead to a deprotection step to provide a compound of formula I in which R ¹ is such as -OH. Thus, one method of preparing a compound of the present invention comprises coupling Compounds 1 and 2, and comprising forming a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The method for preparing Compound 1 is described in the Examples. Compound 2 is generally commercially available or may be prepared using methods known in the art.

Compounds of formula (I) and salts thereof may also be prepared as shown in scheme II:

system II

In the first step, compound 1 is coupled with compound 3, compound 3 is coupled with compound 4, where Y and Z are in situ ( in situ ) to form an R ³ moiety. For example, when R ³ is -C (O) NR ²² R ²³ , Y is -COOH and Z is HNR ²² R ²³ . Alternatively, compound 3 is first coupled with compound 4 and then the resulting compound is coupled with compound 1. As in scheme I, R ¹ is -OCH ₃ or -OCH ₂ CH ₃ In an example of such a group, the coupling step is followed by a deprotection step to provide a compound of formula I wherein R ¹ is —OH. Thus, one method of preparing a compound of the present invention comprises coupling compounds 1, 2 and 3 with an optional deprotection step to form a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Compounds 3 and 4 are generally commercially available or can be prepared using methods known in the art.

Compounds of formula (I) and salts thereof may also be prepared as shown in Formula III below: {based on Example 9}

system III

Again, as in formulas I and II, this is a standard coupling reaction between a compound of formula I and compound 5, wherein R ¹ is —OH, to prepare a compound of formula I wherein R ¹ is —NR ⁸ R ⁹ . to be.

Certain intermediates described herein are novel and therefore it is believed that such compounds are provided as further embodiments of the invention, including, for example, compounds of Formula 1 or salts thereof:

Wherein P ¹ is an amino-protecting group selected from H or t -butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t -butyldimethylsilyl, R ¹ , R ² , R ⁵ , R ⁶ , a and b are as defined for Formula (I). Other intermediates of the invention have the general formula (6) or salts thereof:

,

,

Wherein R ^1P is selected from —OP ³ , —NHP ² , and —NH (OP ⁴ ); P ² is t - butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonylamino ethoxycarbonyl, formyl, trimethylsilyl, and t - butyldimethylsilyl amino protecting group selected from and; P ³ is a carboxy-protecting group selected from methyl, ethyl, t -butyl, benzyl, p -methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t -butyldimethylsilyl, and diphenylmethyl; P ⁴ is -C _{1 - 6} alkyl, tri C _{1 - 6} alkyl silyl, -C _{1 - 6} alkanoyl, benzoyl, benzyl, p - methoxybenzyl, 9-fluorenyl methyl, and diphenyl selected from methylhydroxy Is a loxyl-protecting group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, b, and X are as defined for Formula (I). Other intermediates of the invention have the general formula (7) and salts thereof:

,

,

Wherein, R ^3P is -C _{0 - 1} is selected from alkylene -COO-P ^3, and ⁴ -OP phenyl substituted with _{- 5} alkylene -OP ^4, -C _0; P ³ is a carboxy-protecting group selected from methyl, ethyl, t -butyl, benzyl, p -methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t -butyldimethylsilyl, and diphenylmethyl; P ⁴ is -C _{1 - 6} alkyl, tri C _{1 - 6} alkyl silyl, -C _{1 - 6} alkanoyl, benzoyl, benzyl, p - methoxybenzyl, 9-fluorenyl methyl, and diphenyl selected from methylhydroxy Is a loxyl-protecting group; R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , a, b, and X are as defined for Formula (I). Another intermediate of the invention has the formula (8) or salts thereof:

,

,

Where R ^4P is -OP ⁴ ; -C _{1 - 2} alkylene -COO-P ^3; And phenyl or benzyl substituted with -COO-P ³ ; P ³ is a carboxy-protecting group selected from methyl, ethyl, t -butyl, benzyl, p -methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t -butyldimethylsilyl, and diphenylmethyl; P ⁴ is -C _{1 - 6} alkyl, tri C _{1 - 6} alkyl silyl, -C _{1 - 6} alkanoyl, benzoyl, benzyl, p - methoxybenzyl, 9-fluorenyl methyl, and diphenyl selected from methylhydroxy Is a loxyl-protecting group; And R ¹ , R ² , R ³ , R ⁵ , R ⁶ , a, b, and X are as defined for Formula (I). Another intermediate of the invention has the formula (9) or salts thereof:

Wherein R ^3P is -C _{0 - 1} is selected from alkylene -COO-P ^3, and phenyl substituted with -OP ⁴ _{- 5} alkylene -OP ^4, -C _0; R ^4P is -OP ⁴ ; -C _{1 - 2} alkylene -COO-P ^3; And phenyl or benzyl substituted with -COO-P ³ ; P ³ is a carboxy-protecting group selected from methyl, ethyl, t -butyl, benzyl, p -methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t -butyldimethylsilyl, and diphenylmethyl; P ⁴ is -C _{1 - 6} alkyl, tri C _{1 - 6} alkyl silyl, -C _{1 - 6} alkanoyl, benzoyl, benzyl, p - methoxybenzyl, 9-fluorenyl methyl, and diphenyl selected from methylhydroxy Is a loxyl-protecting group; R ¹ , R ² , R ⁵ , R ⁶ , a, b, and X are as defined for Formula (I). Thus, the process for preparing the compounds of the present invention involves the step of deprotecting the compounds of formula 1, 6, 7, 8, 9 or salts thereof.

Further details regarding specific reaction conditions and other procedures for preparing exemplary compounds of the present invention or intermediates thereof are described in the Examples set forth below.

Usefulness

The compounds of the present invention have neprilysin (NEP) inhibitory activity, i.e. the compounds can inhibit enzyme-catalytic activity. In another embodiment, the compound does not show significant inhibitory activity of the angiotensin-converting enzyme. One measure of the ability of a compound to inhibit NEP activity is an inhibition constant (pKi).

The pKi value is the negative logarithm of the dissociation constant, Ki, below 10, which is generally reported in moles. Particular objects of the invention are those having a pKi of at least 6.0 in the NEP, in particular having a pKi of at least 7.0, and more particularly having a pKi of at least 8.0. In one embodiment, the compound of interest has a pKi in the range of 6.0-6.9, and in another embodiment, the compound of interest has a pKi in the range of 7.0-7.9; In another embodiment, the target compound has a pKi in the range of 8.0-8.9; In another embodiment, the target compound has a pKi of 9.0 or greater. These values may be determined according to techniques well known in the art and the analysis described herein.

Another measure of the compound's ability to inhibit NEP activity is the apparent inhibition constant, IC ₅₀ , which is the molar concentration of the compound that results in a 50% -maximal inhibition of substrate conversion by the NEP enzyme. )to be. The pIC ₅₀ value is the negative logarithm of IC ₅₀ , with 10 below. Particularly preferred compounds of the present invention include those having a pIC ₅₀ for NEP greater than or equal to about 5.0. The desired compound is also included having a pIC ₅₀ pIC about _50, or about 7.0 or more for at least about 6.0 NEP NEP. In other embodiments, the target compound has a pIC ₅₀ for NEP in the range of about 7.0-11.0; In other embodiments, such as in the range of about 8.0-10.0.

It is noted that in some cases, the compounds of the present invention may have a weak NEP inhibitory activity. In that case, one skilled in the art will also recognize that this compound still has utility as a research tool.

Exemplary assays for determining the properties of compounds of the present invention, such as NEP inhibitory activity, are described in the Examples and include, by way of example and not limitation, assays that measure NEP inhibition (as described in Assay 1). Useful secondary assays include assays that measure ACE inhibition (also described in Assay 1) and aminopeptidase P (APP) inhibition (as disclosed in Sulpizio et al. (2005) JPET 315: 1306-1313). Pharmacodynamic analyzes evaluating in vivo inhibitory potencies for ACE and NEP in anesthetized rats are described in Assay 2 (see also Seymour et al. (1985) Hypertension 7 (Suppl I): I -35-I-42 and Wigle et al. (1992) Can . J. Physiol . Pharmacol . 70: 1525-1528), where ACE inhibition is measured as a percent inhibition of angiotensin I pressor response, and NEP Percent inhibition is measured as increased urinary cyclic guanosine 3 ', 5'-monophosphate (cGMP) output.

There are a number of in vivo assays that can be used to confirm further utility of the compounds of the present invention. Conscious Spontaneous Hypertension Rat (SHR) model is a renin dependent hypertension model and is detailed in Assay 3. Intengan et al. (1999) Circulation 100 (22): 2267-2275 and Badyal et al. (2003) Indian Journal of Pharmacology 35: 349-362. The conscious desoxycorticosterone acetate-salt (DOCA-salt) rat model is a volume dependent hypertension model useful for measuring NEP activity and is detailed in Assay 4. Trapani et al. (1989) J. Cardiovasc . Pharmacol . 14: 419-424, Intengan et al. (1999) Hypertension 34 (4): 907-913, and Badyal et al. (2003) (supra). The DOCA-salt model is particularly useful for assessing the test compound's ability to lower blood pressure and for measuring the test compound's ability to prevent or delay blood pressure rise. Dahl salt-sensive (DSS) hypertensive rat model is a hypertension model that is sensitive to dietary salt (NaCl) and is detailed in Assay 5. Rapp (1982) Hypertesion 4: 753-763. For example, Kato et al. (2008) J. Cardiovasc . Pharmacol . The rat monocrotaline model of pulmonary arterial hypertension, described in 51 (1): 18-23, is a reliable predictor of clinical efficacy for the treatment of pulmonary arterial hypertension. Heart failure animal models include the DSS rat model for heart failure and the aorto-caval fistula (AV shunt) model, the latter being described, for example, in Norling et al. (1996) J. Amer . Soc . Nephrol . 7: 1038-1044. Other animal models, such as hot plates, tail-flick and formalin tests, and spinal nerve ligation (SNL) models of neuropathic pain are known as analgesics of the compounds of the invention. can be used to measure analgesic characteristics. For example, Malmberg et al. (1999) Current Protocols in See Neuroscience 8.9.1-8.9.15.

The compounds of the present invention are expected to inhibit NEP enzymes in the assays listed above or in analysis of similar properties. Thus, the above-described assays are useful for determining the therapeutic utility of the compounds of the invention, for example, as an antihypertensive agent or antidiarrheal agent. Other characteristics and utility of the compounds of the present invention can be demonstrated using other in vitro and in vivo assays well known to those skilled in the art. Compounds of formula (I) can be active drugs and prodrugs. Thus, when discussing the activity of a compound of the invention, it is understood that the prodrug may not exhibit the activity expected in the assay, but once metabolized it is expected to exhibit the desired activity.

The compounds of the present invention are expected to be useful for the treatment and / or prevention of diseases in response to NEP inhibition. Thus, it is expected that patients suffering from a disease or disorder treated by increasing NEP enzyme inhibition or increasing the level of its peptide substrate may be treated by administering a therapeutically effective amount of a compound of the present invention. For example, by inhibiting NEP, the compound is a natriuretic peptide, bombesin, bradykinin, calcitonin, endothelin, enkephalin, neurotensin ), It is expected to enhance the biological effects of endogenous peptides metabolized by NEP, such as substance P and vasoactive intestinal peptides. Thus, such compounds are expected to have other physiological actions on, for example, the renal system, central nervous system, reproductive system and gastrointestinal system.

In one embodiment of the invention, patients suffering from diseases or disorders treated by inhibiting NEP enzymes are those compounds of the invention in their active form, ie, R ¹ is -OR ⁷ and -NR ⁸ R ^Is selected from ⁹ , R ⁷ is H, R ⁸ is H or -OH, R ⁹ is H, and R ² -R ⁶ , a, b, and X are as defined for Formula I; It is treated by administering a compound of I.

In another embodiment, patients are treated by administering a compound that is metabolized in vitro to form a compound of Formula I, wherein R ¹ is selected from -OR ⁷ and -NR ⁸ R ⁹ , and R ⁷ is H , R ⁸ is H or -OH, R ⁹ is H, and R ² -R ⁶ , a, b, and X are as defined for formula (I). In an exemplary embodiment, patients are treated by administering a compound that forms a compound of Formula III wherein R ¹ is -OR ⁷ and R ⁷ is H in vitro.

In another embodiment, patients are treated by administering a compound of the invention, that is, a compound of Formula I, in its prodrug form at stage R ¹ , wherein:

R ¹ is -OR ⁷ ; R ⁷ is -C _{1 - 8} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - [( _{CH 2) 2 O] 1-3 CH} 3, -C 1 - 6 alkylene group ^{-OC (O) R 10, -C} 1 - 6 alkylene -NR ¹² R ^13, -C _1-6 alkylene -C ( _{^{O) R 31, -C 0 -}} 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

, 및

으로부터 선택되거나; 또는

,

, And

; or

R ¹ is —NR ⁸ R ⁹ ; R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ⁹ is H; or

R ¹ is —NR ⁸ R ⁹ ; R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ⁹ is -C _{1 - 6} alkyl or -C (O) R ¹⁷ a;

R ¹ is —NR ⁸ R ⁹ ; R ⁸ is selected from H or -OH; R ⁹ is -C _{1 - 6} is selected from alkyl, and -C (O) R ^17;

R ¹ is —OR ⁷ and R ² is taken together with R ⁷ to form —CR ¹⁸ R ¹⁹ —; or

R ¹ is —NR ⁸ R ⁹ and R ² is taken together with R ⁸ to form —C (O) —;

R ¹⁰ , R ¹² -R ¹⁷ , R ³¹ , R ³² , R ³ -R ⁶ , a, b, and X are as defined for Formula (I). In an exemplary embodiment, the patients are in prodrug form thereof at R ¹ and are treated by administering a compound of the invention having Formula III.

Cardiovascular disease

By enhancing the effects of vasoactive peptides such as natriuretic peptides and bradykinin, the compounds of the present invention have utility in treating and / or preventing medical conditions such as cardiovascular diseases. It is expected to find. For example, Roques et al. (1993) Pharmacol . Rev. 45: 87-146 and Dempsey et al. (2009) Amer . J. of Pathology 174 (3): 782-796. Particularly interesting cardiovascular diseases include hypertension and heart failure. Hypertension includes, but is not limited to, primary hypertension, also referred to as essential hypertension or idiopathic hypertension; Secondary hypertension; Hypertension with kidney disease; Severe hypertension with or without kidney disease; Pulmonary hypertension, including pulmonary arterial hypertension; And resistant hypertension. Heart failure includes, by way of example and not limitation, congestive heart failure, acute heart failure; For example, chronic heart failure (also referred to as systolic heart failure) with reduced left ventricular ejection fraction or chronic heart failure (or with conserved left ventricular ejection rate) Also referred to as diastolic heart failure); And acute and chronic non-compromised heart failure with or without renal disease. Thus, one embodiment of the invention relates to a method of treating hypertension, in particular primary hypertension or pulmonary arterial hypertension, comprising administering to a patient a therapeutically effective amount of a compound of the invention.

In the treatment of primary hypertension, the therapeutically effective amount is generally sufficient to lower the patient ' s blood pressure. This includes both mild-to-moderate hypertension and severe hypertension. When used to treat high blood pressure, the compounds of the present invention are aldosterone antagonists, aldosterone synthase inhibitors, angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzymes / neprilysine inhibitors, angiotensin-converting enzymes. 2 (ACE2) activators and stimulators, angiotensin-II vaccines, anti-diabetic agents, anti-lipid agents, anti-thrombotic agents, AT ₁ receptor antagonist and dual-acting AT ₁ receptor antagonist / neprilysine inhibitor, β ₁ -adrenergic receptor antagonist, dual-acting β-adrenergic receptor antagonist / α ₁ -receptor antagonist, calcium channel blocker, diuretic , Endothelin receptor antagonists, endothelin converting enzyme inhibitors, neprilysin inhibitors, natriuretic peptides and analogues thereof, natriuretic peptide removal receptor antagonists (natriuret) ic peptide clearance receptor antagonists, nitric oxide donors, non-steroidal anti-inflammatory agents, phosphodiesterase inhibitors (particularly PDE-V inhibitors), prostaglandin receptor agonists, renin It can be administered in combination with other therapeutic agents, such as inhibitors, soluble guanylate cyclase stimulants and activators, and combinations thereof. In one specific embodiment of the invention, the compounds of the invention are used in combination with AT ₁ receptor antagonists, calcium channel blockers, diuretics or combinations thereof to treat primary hypertension. In another specific embodiment of the invention, the compounds of the invention are used in combination with AT ₁ receptor antagonists to treat hypertension involving kidney disease. When the compound is used in the treatment of resistant hypertension, it may be administered in combination with other therapeutic agents such as aldosterone synthase inhibitors.

In the treatment of pulmonary arterial hypertension, the therapeutically effective amount is generally sufficient to lower pulmonary vascular resistance. Another goal of treatment is to improve the patient's motor skills. For example, in a clinical setting, the therapeutically effective amount may be an amount that enhances the patient's ability to walk comfortably for a period of 6 minutes (covering a distance of approximately 20-30 meters). . When the compounds of the present invention are used to treat pulmonary arterial hypertension, they are α adrenergic receptor antagonists, β ₁ -adrenergic receptor antagonists, β ₂ -adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, anticoagulant, calcium It may be administered in combination with other therapeutic agents such as channel blockers, diuretics, endothelin receptor antagonists, PDE-V inhibitors, prostaglandin analogs, selective serotonin reuptake inhibitors, and combinations thereof. In one particular embodiment of the invention, the compounds of the present invention can be used to treat pulmonary arterial hypertension in combination with a PDE-V inhibitor or a selective serotonin reuptake inhibitor.

Another embodiment of the invention relates to a method of treating heart failure, in particular congestive heart failure (including both contractile and diastolic congestive heart failure), comprising administering to a patient a therapeutically effective amount of a compound of the invention. . In general, a therapeutically effective amount is an amount sufficient to lower blood pressure and / or improve renal function. At the clinical site, therapeutically effective amounts improve cardiac hemodynamics of the heart, such as, for example, wedge pressure, right atrial pressure, filling pressure, and decreased vascular resistance. It may be sufficient amount to make. In one embodiment, the compound is administered as an intravenous dosage form. When the compounds are used to treat heart failure, they are adenosine receptor antagonists, advanced glycation end product breakers, aldosterone antagonists, AT ₁ receptor antagonists, β ₁ -adrenergic receptor antagonists, dual-acting β-adrenergic Sex receptor antagonists / α ₁ -receptor antagonists, chymase inhibitors, digoxin, diuretics, endothelin converting enzyme (ECE) inhibitors, endothelin receptor antagonists, natriuretic peptides and analogues thereof, natriuretic peptide elimination receptors It can be administered in combination with other therapeutic agents, such as antagonists, nitric oxide donors, prostaglandin analogs, PDE-V inhibitors, soluble guanylate cyclase activators and stimulants, and vasopressin receptor antagonists. In one embodiment of the invention, the compounds of the invention are used in the treatment of congestive heart failure in combination with aldosterone antagonists, β ₁ -adrenergic receptor antagonists, AT ₁ receptor antagonists, or diuretics.

diarrhea

As NEP inhibitors, the compounds of the present invention are expected to inhibit the degradation of endogenous enkephalin, and therefore such compounds are also used in the treatment of diarrhea, including infectious and secretory / watery diarrhea. Usefulness can be found. See, eg, Baumer et al. (1992) Gut 33: 753-758; Farthing (2006) Digestive Diseases 24: 47-58; And Marcais-Collado (1987) Eur . J. Pharmacol. See 144 (2): 125-132. When a compound of the present invention is used to treat diarrhea, it may be combined with one or more additional antidiarrheal agents.

Kidney disease

By enhancing the effect of vasoactive peptides, such as sodium diuretic peptide and bradykinin, the compounds of the present invention enhance renal function (Chen et al. (1999) Circulation 100: 2443-2448; Lipkin et al. ) Kidney Int . 52: 792-801; And Dussaule et al . (1993) Clin . Sci . 84: 31-39), and is expected to find utility in treating and / or preventing renal disease. Particularly interesting kidney diseases include diabetic nephropathy, chronic kidney disease, proteinuria, and in particular acute kidney injury or acute renal failure Sharkovska, etc. (2011) Clin Lab 57:. . 507-515 and Newaz, etc. (2010) Renal Failure 32: 384-390). When the compounds of the present invention are used to treat kidney disease, they can be administered in combination with other therapeutic agents such as angiotensin-converting enzyme inhibitors, AT ₁ receptor antagonists, and diuretics.

Prophylaxis ( Preventative Therapy )

By enhancing the efficacy of sodium diuretic peptides, the compounds of the present invention can also be used in prophylactic therapy (Potter et al., (2009) Handbook ) due to antihypertrophic and antifibrotic effects of sodium diuretic peptides of Experimental Pharmacology 191: 341-366), e.g. prevent cardiac insufficiency from progressing after myocardial infarction, prevent arterial restenosis after angioplasty, vascular operation It is expected to be useful for preventing thickening of blood vessel walls, preventing atherosclerosis, and diabetic angiopathy.

glaucoma( Glaucoma )

The compounds of the present invention are expected to be useful in treating glaucoma by enhancing the effect of sodium diuretic peptides. See, for example, Diestelhorst et al. (1989) International Ophthalmology 12: 99-101. When the compounds of the present invention are used to treat glaucoma, it may be combined with one or more additional antiglaucoma agents.

Pain relief Pain Relief )

As NEP inhibitors, the compounds of the present invention are expected to inhibit the degradation of endogenous enkephalins, and thus such compounds may also find utility as analgesic. For example, Roques et al. (1980) Nature 288: 286-288 and Thanawala et al. (2008) Current See Drug Targets 9: 887-894. When the compounds of the present invention are used for the treatment of pain, they are aminopeptidase N or dipeptidyl peptidase III inhibitors, non-steroidal anti-inflammatory agents, monoamine reuptake inhibitors, muscle relaxants, NMDA It can be combined with one or more additional antinociceptive drugs such as receptor antagonists, opioid receptor agonists, 5-HT _1D serotonin receptor agonists, and tricyclic antidepressants.

Other usability

Since NEP inhibition properties, compounds of the invention may also cough (antitussive agent) is expected to be useful as liver cirrhosis (liver cirrhosis) and context related hypertension (portal hypertension) (Sansoe the like (2005) J. Hepatol 43.: 791-798), cancer (Vesely (2005) J. Investigative Med . 53: 360-365), depression (Noble et al. (2007) Exp . Opin . Ther . Targets 11: 145-159), menstrual disorders, preterm labor, pre-eclampsia , Endometriosis, reproductive disorders (eg, infertility in men and women, polycystic ovarian syndrome, implantation failure), and male erectile Usefulness can be found in the treatment of male and female sexual dysfunction, including dysfunction and female arousal disorders. More specifically, the compounds of the present invention are expected to be useful in the treatment of female sexual dysfunction, often defined as difficulty or inability to find satisfaction in the sexual expression of female patients (Pryde et al . (2006) J. Med . Chem 49: reference 4409-4424). This is a non-limiting example and includes a number of various female sexual disorders, including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, and sexual pain disorder. Include. When used in the treatment of such disorders, especially female sexual dysfunction, the compounds of the present invention may be combined with one or more of the following second agents: PDE-V inhibitors, dopamine agonists, estrogen receptor agonists and And / or antagonists, and androgens and estrogens. Because of the NEP inhibitory properties, the compounds of the present invention are also expected to have anti-inflammatory properties, especially when used in combination with statins.

Recent studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and diet induced obesity. See Coppey et al. (2011) Neuropharmacology 60: 259-266. Therefore, because of the NEP inhibitory properties, the compounds of the present invention are also expected to be useful for providing protection from nerve damage due to diabetes or diet induced obesity.

The amount of the compound of the present invention administered per dose or the total amount administered per day is predetermined or the nature and severity of the patient's condition, the condition to be treated, the patient's age, weight and general health A number of factors, including pharmacological considerations such as the patient's tolerance to the active agent, the route of administration, the activity, efficacy, pharmacokinetics and toxicological profiles of the compound and the second agent administered These may be determined according to individual patients in consideration of the above. Treatment of a patient suffering from a disease or medical condition (such as hypertension) can begin with a predetermined dose or a dose determined by the treating physician and is necessary to prevent, ameliorate, suppress or alleviate the symptoms of the disease or medical condition. Will last for a period. Patients receiving such treatment will generally be routinely monitored to determine the effectiveness of the therapy. For example, in the treatment of hypertension, blood pressure measurements can be used to determine the effectiveness of the treatment. Similar indicators for other diseases and conditions described herein are well known and readily available to the treating physician. Continuous monitoring by the physician will ensure that the optimal amount of a compound of the present invention is administered at any given time and will facilitate the determination of the duration of treatment. This is particularly important because secondary agents may also need to be adjusted if administered, as well as their selection, dosage, and duration of treatment. In this way, treatment regimens and dosing schedules are administered throughout the course of treatment, such that a minimum amount of active agent is administered that exhibits the desired effect, and that the administration can only last for a period of time necessary to successfully treat the disease or medical condition. Can be adjusted over time.

Research tools

      Since the compounds of the present invention have NEP enzyme inhibitory activity, such compounds are useful for investigating or studying biological systems or samples with NEP enzymes, for example to study diseases in which NEP enzymes or peptide substrates play a role. It is useful as a research tool. Any suitable biological system or sample having a NEP enzyme can be used in such studies, which can be performed in vitro or in vivo. Representative biological systems or samples suitable for such studies include cells, cell extracts, plasma membranes, tissue samples, extracted organs, mammals (such as mice, rats, guinea pigs, rabbits, dogs, pigs, But are not limited to, mammals. In one specific embodiment of the invention, NEP enzyme activity in mammals is inhibited by administering an NEP-inhibitory amount of a compound of the invention. The compounds of the present invention can also be used as research tools by performing biological assays using such compounds.

When used as a research means, biological systems or samples comprising NEP enzymes will generally come in contact with the NEP enzyme-inhibited amounts of the compounds of the invention. After the biological system or sample is exposed to the compound, the inhibitory effect of the NEP enzyme may be determined by conventional methods, such as measuring receptor binding in a binding assay or measuring ligand-mediated changes in a functional assay. And using the equipment. The exposure may comprise contacting a cell or tissue with the compound and administering the compound to a mammal, eg, intraperitoneal (ip), oral (po), intravenous (iv), subcutaneous (sc) or inhaled Administration, and the like. This determining step may involve measuring the response (quantitative analysis) or may involve observation (qualitative analysis). Measuring the reaction may include, for example, measuring the effect of the compound on the biological system or sample using conventional methods and equipment, such as enzyme activity assays, and product mediated changes in functional assays. ) Is measured. The results of the assay can be used to determine the amount of compound needed to achieve the desired result, ie the amount of NEP enzyme-inhibition and activity. In general, the determining step will include determining the effect of inhibiting the NEP enzyme.

In addition, the compounds of the present invention can be used as research means for evaluating other compounds and are therefore also useful for screening assays to find novel compounds with, for example, NEP inhibitory activity. In this way, the compounds of the present invention can be used as a standard in the assay to allow comparison of the test compound and the results obtained by the compounds of the present invention, providing binding or superior activity, if capable of binding. It allows the identification of the test compound having. For example, the Ki data for a test compound or a group of test compounds may be used to identify test compounds having desired properties, eg, test compounds with approximately the same or superior pKi values as the compounds of the present invention. It is compared with pKi data for compounds of. This aspect of the invention includes, as a separate embodiment, the generation of comparative data (using appropriate assays) and analysis of test data to identify a test compound of interest. Thus, the test compound can be evaluated in the biological assay by a method comprising the following steps: (a) performing a biological assay with the test compound to provide a first assay value; (b) conducting a biological assay with a compound of the present invention to provide a second assay value; Wherein step (a) is performed before, after or simultaneously with step (b); And (c) comparing the first analysis value obtained from step (a) with the second analysis value obtained from step (b). Representative biological assays include NEP enzyme inhibition assays.

Pharmaceutical Compositions and Formulations

The compounds of the present invention are generally administered to a patient in the form of a pharmaceutical composition or formulation. Such pharmaceutical compositions may be administered to a patient via an acceptable route including, but not limited to, oral, rectal, vaginal, nasal, inhalation, topical (including transdermal), ocular, and parenteral have. In addition, the compounds of the present invention may be administered orally, for example, in multiple doses per day (for example, twice, three or four times a day), single daily dose ) Or a single weekly dose. It is contemplated that any of the forms of the compounds of the present invention (i.e., free bases, free acids, pharmaceutically acceptable salts, solvates, etc.) suitable for a particular mode of administration may be used in the pharmaceutical compositions discussed herein It will be understood.

Thus, in one embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present invention. The composition may, if desired, contain other therapeutic and / or formulating agents. When discussing a composition, "compound of the invention" may also be referred to herein as an "active agent" to distinguish it from other components of the formulation, such as a carrier. . Thus, the term "active agent" is understood to include compounds of formula I and pharmaceutically acceptable salts, solvates and prodrugs of said compounds.

 The pharmaceutical compositions of the present invention generally comprise a therapeutically effective amount of a compound of the invention. One skilled in the art will recognize, however, that the pharmaceutical composition may contain more than a therapeutically effective amount, such as in a bulk composition, or may be administered in a therapeutically effective amount, that is, an individual unit dose designed for multi- As will be understood by those skilled in the art. Generally, the composition will contain about 0.01-95 wt% of the active agent, including about 0.01-30 wt%, such as about 0.01-10 wt%, the actual amount depending on the formulation itself, route of administration, frequency of administration, etc. Will be. In one embodiment, a composition suitable for oral dosage form contains, for example, about 5-70 wt% or about 10-60 wt% of the active agent.

Conventional conventional carriers or excipients may be used in the pharmaceutical compositions of the present invention. The choice of particular carrier or excipient, or the combination of carrier or excipient, will depend upon the mode of administration used to treat the particular patient or type of disease or disease condition. In this regard, the preparation of compositions suitable for the particular mode of administration is well within the purview of those skilled in the pharmaceutical arts. In addition, the carriers or excipients used in such compositions are commercially available. As a further example, conventional formulation techniques are described in Remington : The Science and Practice of Pharmacy , 20th edition, Lippincott Williams & White, Baltimore, Maryland (2000); And HC Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems , 7th edition, Lippincott Williams & White, Baltimore, Maryland (1999).

Representative examples of materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Celluloses such as microcrystalline cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; Malt; gelatin; Talc; Excipients such as cocoa butter, and suppository waxes; Oils such as peanut oil, cottonseed oil, safflower seed oil, sesame oil, olive oil, corn oil and soybean oil; Glycols, such as propylene glycol; Polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; Esters, such as ethyl oleate and ethyl laurate; Agar; Buffering agents, such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; ethyl alcohol; Phosphate buffer solution; Compressed propellant gases, such as chlorofluorocarbons and hydrofluorocarbons; And other non-toxic compatible materials used in pharmaceutical compositions.

Pharmaceutical compositions are generally prepared by mixing or blending the active agent completely and intimately with a pharmaceutically acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture is then molded or loaded into tablets, capsules, pills, canisters, cartridges, dispensers, etc. using conventional methods and equipment. Can be.

In one embodiment, the pharmaceutical composition is suitable for oral administration. Compositions suitable for oral administration include capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; Solutions or suspensions in aqueous or non-aqueous liquids; Oil-in-water or water-in-oil liquid emulsions; Formulations such as elixir or syrup, each containing a predetermined amount of active agent.

When intended for oral administration as a solid dosage form (capsules, tablets, pills, etc.), the composition will generally include the active agent and one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate. Solid dosage forms also include fillers or extenders, such as starch, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; Binders, such as carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; Humectants, such as glycerol; Disdintegraging agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and / or sodium carbonate; A solution retarding agent such as paraffin; Absorption accelerators, such as quaternary ammonium compounds; Wetting agents, such as cetyl alcohol and / or glycerol monostearate; Absorbents, such as kaolin and / or bentonite clays; Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and / or mixtures thereof; coloring agent; And buffers.

Release agents, wetting agents, coatings, sweeteners, flavoring agents and perfuming agents, preservatives and antioxidants may also be present in the pharmaceutical compositions. Exemplary coating agents for tablets, capsules, pills, and the like, include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, cellulose acetate trimellitate, carboxymethyl ethyl And those used for enteric coating purposes, such as cellulose, hydroxypropyl methyl cellulose acetate succinate and the like. Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite, and the like; Fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol and the like; And metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid, phosphoric acid, and the like.

The composition may be formulated to provide slow or controlled release of the active agent, using, for example, various ratios of hydroxypropyl methyl cellulose or other polymer matrices, liposomes and / or microspheres. In addition, the pharmaceutical compositions of the present invention may contain an opacifying agent and may be formulated to release the active agent in a predetermined portion of the gastrointestinal tract, optionally only in a delayed manner, or only preferentially. Examples of embedding compositions that can be used include polymeric substances and waxes. The active agent may also be a micro-encapsulated formulation, optionally with one or more of the aforementioned excipients.

Suitable liquid dosage forms for oral administration include, by way of example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms are generally active agents, and inert diluents such as, for example, water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 Butylene glycol, oils (eg, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, And solubilizing agents and emulsifiers such as mixtures thereof. Suspensions are suspended, for example, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxy, bentonite, agar-agar and tragacanth, and mixtures thereof. It may include a suspending agent.

For the purpose of oral administration, the pharmaceutical compositions of the invention may be packaged in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable for administration to a patient, ie each unit is calculated to produce the desired therapeutic effect, alone or in combination with one or more additional units. Containing a predetermined amount of the active agent. For example, such unit dosage forms can be capsules, tablets, pills, and the like.

In another embodiment, the compositions of the present invention are suitable for inhalation administration and will generally be in the form of aerosols or powders. Such compositions are generally administered using well known delivery devices, such as a nebulizer, a dry powder inhaler, or a metered-dose inhaler. The nebulizer produces a high velocity air stream that causes the composition to be sprayed as a mist that is carried into the patient's respiratory tract. Exemplary spray formulations include active agents that dissolve in the carrier to form a solution or micronized and combined with the carrier to form a suspension of micronized particles of respirable size. Dry powder inhalers administer the active agent as a free flowing powder that is dispersed in the patient's airflow during inhalation. Exemplary dry powder formulations are dry-mixed with excipients such as lactose, starch, mannitol, dextrose, polylactic acid, polylactide-co-glycolide, and combinations thereof. blended) active agent. The metered dose inhaler uses a compressed propellant gas to discharge a measured amount of active agent. Exemplary metered-dose formulations include solutions or suspensions of the active agent in liquefied propellants, such as chlorofluorocarbons or hydrofluoroalkanes. Optional components of such formulations include co-solvents such as ethanol or pentane, and interfaces such as sorbitan trioleate, oleic acid, lecithin, glycerin and sodium lauryl sulfate Active agents. Such a composition is generally prepared by adding a cooled or pressurized hydrofluoroalkane to a suitable container containing an activator, ethanol (if present), and a surfactant (if present). To prepare a suspension, the active agent is micronized and then combined with the propellant. Alternatively, suspension formulations may be prepared by spray drying a surfactant coating on the micronized particles of the active agent. The formulation is then loaded into an aerosol canister to form part of the inhaler.

The compounds of the present invention may also be administered parenterally (e. G., By subcutaneous, intravenous, intramuscular, or intraperitoneal injection). For such administration, the active agents are provided in sterile solutions, suspensions or emulsions. Exemplary solvents for preparing such formulations include water, saline, low molecular weight alcohols such as propylene glycol, polyethylene glycols, oils, gelatin, fatty acid esters such as ethyl oleate, and the like. Parenteral preparations may also contain one or more antioxidants, solubilizers, stabilizers, preservatives, wetting agents, emulsifiers and dispersing agents. Surfactants, additional stabilizers or pH adjusting agents (acids, bases or buffers) and antioxidants are particularly useful for imparting stability to the formulation, for example hydrolysis of the ester and amide linkage that may be present in the compound Which is useful for minimizing or avoiding. These preparations can be made sterile using a sterile injectable medium, a sterilizing agent, filtration, irradiation or heat. In one specific embodiment, the parenteral preparation comprises an aqueous cyclodextrin solution as a pharmaceutically acceptable carrier. Suitable cyclodextrins are those having six or more α-D-glucopyranose units, linked at the 1,4 position by binding such as in amylase, β-cyclodextrin or cycloheptaamylose. It includes a click molecule. Exemplary cyclodextrins include cyclodextrin derivatives such as hydroxypropyl and sulfobutyl ether cyclodextrins, such as hydroxypropyl-β-cyclodextrin and sulfobutyl ether β-cyclodextrin. Exemplary buffers for such formulations include carboxylic acid-based buffers such as citrate, lactate and maleate buffer solutions.

The compounds of the present invention may also be administered transdermally using known transdermal delivery systems and excipients. For example, the compound may be mixed with a permeation enhancer such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-one, and the like, and incorporated into a patch or similar delivery system. have. Additional excipients, including gelling agents, emulsifiers, and buffers, if desired, may be used in such transdermal compositions.

Secondary agents ( Secondary Agents )

The compounds of the present invention may be useful as sole treatment of a disease and may be combined with one or more additional therapeutic agents to achieve the desired therapeutic effect. Thus, in one embodiment, the pharmaceutical compositions of the present invention comprise other drugs co-administered with the compounds of the present invention. For example, the composition may further comprise one or more drugs (also referred to as "secondary agent (s)"). Such therapeutic agents are well known in the art and include adenosine receptor antagonists, α-adrenergic receptor antagonists, β ₁ -adrenergic receptor antagonists, β ₂ -adrenergic receptor agonists, dual-acting β-adrenergic receptor antagonists / α ₁ Receptor antagonists, advanced glycation end product breakers, aldosterone antagonists, aldosterone synthase inhibitors, aminoptidase N inhibitors, androgens, angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzymes / Neprilysin inhibitors, angiotensin-converting enzyme 2 activators and stimulants, angiotensin-II vaccines, anticoagulants, anti-diabetics, anti-diabetics, anti-glaucoma agents, anti-lipids, antinociceptive agents ), Thrombolytics, AT ₁ receptor antagonists and dual-acting AT ₁ receptor antagonists / neprilysine inhibitors and multifunctional angiotensin Receptor blockers, bradykinin receptor antagonists, calcium channel blockers, kinase inhibitors, digoxin, diuretics, dopamine agonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, HMG-CoA reductase inhibitors, estrogens , Estrogen receptor agonists and / or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and analogs thereof, natriuretic peptide removal receptor antagonists, neprilysin inhibitors, nitric oxide donors, non-steroidal Anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterase inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium Channel blockers, soluble guanylate cyclase stimulators and activators, tricycles Rick antidepressants, vasopressin receptor antagonists, and combinations thereof. Specific examples of such agents are detailed herein.

Thus, in another embodiment of the present invention, the pharmaceutical composition comprises a compound of the present invention, a second active agent, and a pharmaceutically acceptable carrier. Active agents such as third, fourth, and the like may also be included in the composition. In combination therapy, the amount of the compound of the invention administered and the amount of the secondary agent may be less than the amount normally administered in monotherapy.

Compounds of the present invention may be physically mixed with a second active agent to form a composition comprising both agents; Or each agent may be present in a separate separate composition administered to the patient at the same time or at separate times. For example, a compound of the present invention can be combined with a second active agent using conventional methods and equipment to form a combination of active agents, including a compound of the present invention and a second active agent. In addition, the active agents can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition comprising a compound of the invention, a second active agent and a pharmaceutically acceptable carrier. In this embodiment, the components of the composition are generally mixed or blended to produce a physical mixture. The physical mixture is then administered in a therapeutically effective amount using any of the routes described herein.

Alternatively, the active agents can maintain a separate and distinct state before being administered to the patient. In this embodiment, the agents are not physically mixed together prior to administration, but are administered as separate compositions, simultaneously or at separate times. Such compositions may be packaged separately or packaged together in a kit. When administered at separate times, the second agent will typically be administered within 24 hours after administration of the compound of the invention, at any time from the same time as the administration of the compound of the invention to about 24 hours after administration. . This is also referred to as sequential administration. Thus, the compounds of the present invention may be administered orally simultaneously with one other active agent or sequentially, using two tablets, one tablet for each active agent, where sequential is immediately after administration of a compound of the present invention, or predetermined It can mean administered after a lapse of time (eg, after 1 hour or after 3 hours). It is also contemplated that the second agent may be administered 24 hours after administration of the compound of the present invention. Alternatively, the combination may be administered by different routes of administration, ie one may be administered orally and the other by inhalation.

In one embodiment, the kit comprises an amount sufficient to practice a method of the invention with a first dosage form comprising a compound of the invention, and one or more additional dosage forms comprising one or more of the second agents provided herein. Include as. The first dosage form and the second (or third, etc.) dosage form together comprise a therapeutically effective amount of active agents for the treatment or prevention of a disease or medical condition of a patient.

When included, the second agent (s) are present in a therapeutically effective amount, so that they can generally be administered in an amount that produces a therapeutically beneficial effect when co-administered with a compound of the present invention. The second agent may be in the form of a pharmaceutically acceptable salt, solvate, optionally pure stereoisomers, and the like. The second agent may also be in the form of a prodrug such as a compound having esterified carboxylic acid groups. Accordingly, the second agents listed herein are intended to include all such forms and are either commercially available or can be prepared using conventional methods and reagents.

In one embodiment, the compounds of the present invention are administered in combination with adenosine receptor antagonists, representative examples of which are naxifylline, rolofylline, SLV-320, theophylline, and toapofylline ), But is not limited thereto.

In one embodiment, the compounds of the present invention are administered in combination with an α-adrenergic receptor antagonist, representative examples of which are doxazosin, prazosin, tamsulosin, and terazosin. ), But is not limited thereto.

The compounds of the invention are also β ₁ - can be administered to ( "blockers β _1") and a combination of adrenergic receptor antagonists. Representative beta ₁ -blockers include, but are not limited to, acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, ), Bevantolol, bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, Bupranolol, bubridine, butofilolol, carazolol, carteolol, carvedilol, celiprolol, theta, and the like. But are not limited to, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetolol, levobunolol, Mepindolol, metipranolol, metoprolol succinate and metoprolol tartrate such as metoprolol tartrate. l), moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol, penbutolol, The compounds of the present invention may be used in combination with one or more pharmaceutically acceptable excipients such as perbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sufinalol, talindol, but are not limited to, tertatolol, tilisolol, timolol, toliprolol, xibenolol, and combinations thereof. In one specific embodiment, the β ₁ -antagonist is selected from atenolol, bisoprolol, metoprolol, propranolol, sotalol, and combinations thereof. Generally, the β ₁ -blocker will be administered in an amount sufficient to provide about 2-900 mg in a single dose.

In one embodiment, the compounds of the present invention are administered in combination with a β ₂ -adrenergic receptor agonist, representative examples of which include albuterol, bitolterol, fenoterol, formoterol ( formoterol, indacaterol, isoetharine, levalbuterol, metaproterenol, pirbuterol, pirbuterol, salbutamol, salmefamol ), Salmeterol, terbutaline, vilanterol and the like. In general, the β ₂ -adrenergic receptor agonist will be administered in an amount sufficient to provide 0.05-500 μg per dose.

In one embodiment, the compounds of the present invention are administered in combination with a final glycosylation product (AGE) degrading agent, examples of which include, but are not limited to, allagebrium (or ALT-711), and TRC4149. Include.

In another embodiment, the compounds of the present invention are administered in combination with aldosterol antagonists, representative examples of which include, but are not limited to, eplerenone, spironolactone, and combinations thereof. Generally, the aldosterone antagonist will be administered in an amount sufficient to provide about 5-300 mg per day.

In one embodiment, a compound of the invention is administered in combination with an aminoptidase N or dipeptidyl peptidase III inhibitor, examples of which are non-limiting examples of bestatin and PC18 (2-amino- 4-methylsulfonyl butane thiol, methionine thiol).

Compounds of the invention can also be administered in combination with angiotensin-converting enzyme (ACE) inhibitors. Representative ACE inhibitors include, but are not limited to, acupril, alacepril, benazepril, benazeprilat, captopril, ceranapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, such as lisinopril, moexipril, monopril, moveltopril, pentopril, perindopril, quinapril, quinaprilat, ramipril, but are not limited to, ramipril, ramiprilat, saralasin acetate, spirapril, temocapril, trandolapril, zofenopril, and combinations thereof But is not limited thereto. In certain embodiments, the ACE inhibitor is selected from benazepril, captopril, enalapril, ricinopril, ramipril and combinations thereof. Generally, the ACE inhibitor will be administered in an amount sufficient to provide about 1-150 mg / day.

In another embodiment, the compounds of the present invention are administered in combination with dual-acting angiotensin-converting enzyme / neprilysine (ACE / NEP) inhibitors, examples of which include but are not limited to: AVE-0848 ( (4S, 7S, 12 bR ) -7- [3-methyl-2 (S) -sulfanylbutyramido] -6-oxo-1,2,3,4,6,7,8,12b-octahydro Pyrido [2,1-a] [2] -benzazepine-4-carboxylic acid); AVE-7688 (ilepatryl) and its parent compound; BMS-182657 (2- [2-oxo-3 (S) -[3-phenyl-2 (S) -sulfanylpropionamido] -2,3,4,5-tetrahydro-1H-1-benzase Pin-1-yl] acetic acid); CGS-26303 ([N- [2- (biphenyl-4-yl) -1 (S) -(1H-tetrazol-5-yl) ethyl] amino] methylphosphonic acid); CGS-35601 (N- [1- [4-methyl-2 (S) -sulfanylpentaneamido] cyclopentylcarbonyl] -L-tryptophan); Fasidotril; Pacidotrilate; Enalaprilat; ER-32935 ((3R, 6S, 9aR) -6- [3 (S) -methyl-2 (S) -sulfanylpentaneamido] -5-oxoperhydrothiazolo [3,2-a] azepine -3-carboxylic acid); Gempatrilat; MDL-101264 ((4S, 7S, 12bR) -7- [2 (S) -(2-morpholinoacetylthio) -3-phenylpropionamido] -6-oxo-1,2,3,4, 6,7,8,12b-octahydropyrido [2,1-a] [2] benzazepine-4-carboxylic acid); MDL-101287 ([4S- [4α, 7α (R *), 12bβ] -7- [2- (carboxymethyl) -3-phenylpropionamido] -6-oxo-1,2,3,4,6 , 7,8,12b-octahydropyrido [2,1-a] [2] benzazepine-4-carboxylic acid); Omapatrilat; RB-105 (N- [2 (S) -(mercaptomethyl) -3 (R) -phenylbutyl] -L-alanine); Sampatrilat; SA-898 ( (2R, 4R) -N- [2- (2-hydroxyphenyl) -3- (3-mercaptopropionyl) thiazolidin-4-ylcarbonyl] -L-phenylalanine); Sch-50690 (N- [1 (S) -carboxy-2- [N2- (methanesulfonyl) -L-lysylamino] ethyl] -L-valyl-L-tyrosine); And combinations thereof may also be included. In one specific embodiment, the ACE / NEP inhibitor is selected from: AVE-7688, enalaprill, facidotril, facidotrilate, omapatrilat, sampatrilat, and combinations thereof.

In one embodiment, the compound of the present invention is administered in combination with an angiotensin-converting enzyme 2 (ACE2) activator or stimulant.

In one embodiment, compounds of the invention are administered in combination with an angiotensin-II vaccine, examples of which include, but are not limited to, ATR12181 and CYT006-AngQb.

In one embodiment, a compound of the present invention is administered in combination with an anticoagulant, representative examples of which include, but are not limited to: coumarin, such as warfarin; Heparin; And direct thrombin inhibitors such as argatroban, bivalirudin, dabigatran and lepirudin.

In another embodiment, the compound of the present invention is administered in combination with an anti-diabetic agent. Representative anti-diabetic agents include injectable drugs and orally effective drugs and combinations thereof. Examples of injectable drugs include, but are not limited to, insulin and insulin derivatives. Examples of oral effective drugs include, but are not limited to: biguanides such as metformin; Glucagon antagonists; Α-glucosidase inhibitors such as acarbose and miglitol; Dipeptidyl teptidase IV, such as alogliptin, denagliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin Inhibitors (DPP-IV inhibitors); Meglitinide, such as repaglinide; Oxadiazolidinedione; Sulfonylureas such as chlorpropamide, glimepiride, glipizide, glyburide, and tolazamide; Thiazolidinedione such as pioglitazone and rosiglitazone; And combinations thereof.

In another embodiment, the compound of the present invention is administered in combination with antidiarrheal treatment. Typical treatment options include, but are not limited to, oral rehydration solution (ORS), loperamide, diphenoxylate, and bismuth sabsalicylate.

In another embodiment, the compound of the present invention is administered in combination with an antiglaucoma agent. Representative antiglaucoma agents include, but are not limited to: α-adrenergic agonists such as brimonidine; β ₁ -adrenergic receptor antagonists; Topical β ₁ -blockers such as betaxolol, levobunolol, and timolol; Carbonic anhydrase inhibitors such as acetazolamide, brinzolamide, or dorzolamide; Cholinergic agonists such as cevimeline and DMXB-anabaseine; Epinephrine compounds; Miotics such as pilocarpine; And prostaglandin analogs.

In another embodiment, the compound of the present invention is administered in combination with an anti-lipid agent. Representative anti-lipids include, but are not limited to: cholesteryl ester transfer protein inhibitors (CETP) such as anacetrapib, dalcetrapib, and torcetrapib; Statins such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin; And combinations thereof.

In one embodiment, the compound of the present invention is administered in combination with thrombolytics. Representative thrombolytic agents include, but are not limited to: aspirin; Anti-platelet agents such as clopidogrel, prasugrel, and ticklopidine; Heparin, and combinations thereof.

In one embodiment, the compounds of the present invention are administered in combination with an AT ₁ receptor antagonist, also known as angiotensin II type 1 receptor blocker (ARB). Representative ARBs include abitesartan, azilsartan (e.g., azilsartan medoxyl wheat), benzyllosartan, candesartan, candesartan, candesartan cilexetil ( candesartan cilexetil, elisartan, embusartan, enoltasosartan, eprosartan, EXP3174, fonsartan, forasartan, Glycyllosartan, Irbesartan, Isotheline, Isoteoline, Losartan, Medoximil, Milfasartan, Olmesartan (olmesartan) For example olmesartan medoxyl wheat, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, saralasin, sar Sarmesin, TAK-591, tasosartan, telmisartan, valsartan, zolasartan and these Including, in combination, and the like. In one specific embodiment, the ARB is azilsartan medoxomil, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan medoxomill, irbesartan, saprisartan, Tasosartan, telmisartan, valsartan and combinations thereof. Exemplary salts and / or prodrugs include candensartan cilexetil, eprosartan mesylate, losartan potassium salt, and olmesartan medoxomil. In general, ARB will be administered in an amount sufficient to provide about 4-600 mg per dose, with an exemplary daily dose ranging from 20-320 mg per day.

Compounds of the invention may also be administered in combination with dual-acting agents, such as AT ₁ receptor antagonists / neprilysine inhibitors (ARB / NEP) inhibitors, examples of which include compounds, 4 ′-{ 2-ethoxy-4-ethyl-5-[( (S) -2-mercapto-4-methylpentanoylamino) -methyl] imidazol-1-ylmethyl} -3'-fluorobiphenyl-2- Allegretti et al., Such as carboxylic acids, include, but are not limited to, compounds described in US 2008/0269305 and 2009/0023228, filed April 23, 2008.

Compounds of the invention are also described in Kurtz & Klein (2009) Hypertension As described in Research 32: 826-834, it may be administered in combination with a multifunctional angiotensin receptor blocker.

In one embodiment, the compounds of the present invention are administered in combination with bradykinin receptor antagonists such as icatibant (HOE-140). Such combination therapy is expected to provide the advantage of preventing angioedema or other unwanted consequences of elevated bradykinin levels.

In one embodiment, the compound of the present invention is administered in combination with a calcium channel blocker. Representative calcium channel blockers include, but are not limited to, amlodipine, anipamil, aranipine, barnidipine, bencyclane, benidipine, bepridil, A compound selected from the group consisting of clentiazem, cilnidipine, cinnarizine, diltiazem, efonidipine, elgodipine, etafenone, felodipine, The compounds of the present invention may be used in combination with fendiline, flunarizine, gallopamil, isradipine, lacidipine, lercanidipine, lidoflazine, The present invention relates to the use of nimodipine as an active ingredient in the manufacture of a medicament for the treatment or prevention of diabetes mellitus, for example, lomerizine, manidipine, mibefradil, nicardipine, nifedipine, niguldipine, niludipine, nilvadipine, such as nimodipine, nisoldipine, nitrendipine, nivaldipine, perhexiline, Suramin (prenylamine), Rio when Dean (ryosidine), triangular thiazol dill (semotiadil), Tero dilrin (terodiline), tea Apa mill (tiapamil), verapamil (verapamil), and a combination thereof, but is not limited thereto. In certain embodiments, the calcium channel blocker is amlodipine, befridyl, diltiazem, felodipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, Lycidin, verapamil, and combinations thereof. Generally, the calcium channel blocker will be administered in an amount sufficient to provide about 2-500 mg in a single dose.

In one embodiment, the compounds of the present invention comprise TPC-806 and 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N-[{3 And in combination with a kinase inhibitor, such as, 4-dioxo-1-phenyl-7- (2-pyridyloxy)}-2-heptyl] acetamide (NK3201).

In one embodiment, the compound of the present invention is administered in combination with a diuretic. Representative diuretics include carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide; Acetazolamide, ambuside, azoseride, azosernide, bumetanide, butazolamide, chloraminophenamide, chloraminophenamide, clofenamide, clopa Midlop (clopamide), cloloxolone, disulfamide, ethoxolamide, furosemide, mefruside, metazolamide, pyretanide ( sulfonamide derivatives such as piretanide, torsemide, tripamide, and xipamide, and ethacrynic acid and tienilic acid, indacrinione Loop diuretic, including other phenoxyacetic compounds such as) and quincarbate; Osmotic diuretics, such as mannitol; Potassium-sparing diuretics including aldosterone antagonists such as spironolactone, and Na ⁺ channel inhibitors such as amiloride and triamterene; Althiazide, bendroflumethiazide, benzylhydrochlorothiazide, benzthiazide, butiazide, chlorthalidone, chlorothalidone, chlorothiazide (chlorothiazide), cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, fenquizone, flumethiazide, hydrochlorothia Zide (hydrochlorothiazide), hydroflumethiazide, indapamide, methylclothiazide, meticrane, metolazone, paraflutizide, polyflufluzide Thiazide and thiazide-like diuretics such as polythiazide, quinethazone, teclothiazide, and trichloromethiazide; And combinations thereof, but is not limited thereto. In certain embodiments, the diuretic is amylolide, bumetanide, chlorothiazide, chlortalidone, dichlorphenamide, ethacrynic acid, purosemide, hydrochlorothiazide, hydroflumetiazide, indaffa Mead, methylclothiazide, metolazone, torsemide, triamterene, and combinations thereof. The diuretic will be administered in an amount sufficient to provide about 5-50 mg per day, more generally 6-25 mg per day, with typical dosages of 6.25 mg, 12.5 mg or 25 mg per day.

 Compounds of the invention may also be administered in combination with an endothelin converting enzyme inhibitor (ECE), examples of which include, but are not limited to, phosphoramidon, CGS 26303, and combinations thereof.

In certain embodiments, compounds of the invention are administered in combination with an endothelin receptor antagonist. Representative endothelin receptor antagonists include, but are not limited to, avosentan, ambrisentan, atrasentan, BQ-123, clazosentan, a selective endothelin receptor antagonist that affects the endothelin A receptor, such as darusentan, sitaxentan, and zibotentan; And dual endothelin receptor antagonists affecting both the endothelin A and B receptors, such as bosentan, macitentan, and tezosentan.

In another embodiment, the compounds of the present invention are administered in combination with one or more HMG-CoA reductase inhibitors, also known as statins. Representative statins include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Do not.

In one embodiment, a compound of the present invention is administered in combination with a monoamine reuptake inhibitor, examples of which are non-limiting examples, including atomoxetine, buproprion and buproprion metabolite hydride. Norepinephrine reuptake inhibitors, such as oxybuproprion, maprotiline, reboxetine, and viloxazine; Citalopram and citalopram metabolites desmethylcitalopram, dapoxetine, escitalopram (e.g. escitalopram oxalate), Fluoxetine and Fluoxetine Desmethyl Metabolites norfluoxetine, fluvoxamine (e.g. pulluloxamine maleate), paroxetine, sertraline and sertraline metabolism Selective serotonin reuptake inhibitors (SSRIs) such as water demethylsertraline; Dual serotonin-norepinephrine reuptake inhibitors (SNRIs) such as bicifadine, duloxetine, milnacipran, nefazodone, and venlafaxine; And combinations thereof.

In another embodiment, the compounds of the present invention are administered in combination with muscle relaxants, examples of which include but are not limited to: carisoprodol, chlorzoxazone, cyclobenzaprine ( cyclobenzaprine, diflunisal, metaxalone, metocarbamol, and combinations thereof.

In one embodiment, a compound of the invention is administered in combination with a natriuretic peptide or analog, examples of which include, but are not limited to: carperitide, Nile Therapeutics, CD-NP, CU -NP, nesiritide, PL-3994 (Palatin Technologies, Inc.), ulalitide, senderitide, and Ogawa et al (2004) J. Biol . Chem . 279: 28625-31. Such compounds are also referred to as natriuretic peptide receptor-A (NPR-A) agonists. In another embodiment, compounds of the invention are SC-46542, cANF (4-23), and AP-811 (Veale (2000) Bioorg Med Chem And natriuretic peptide removal receptor (NPR-C) antagonists such as Lett 10: 1949-52). For example, AP-811 shows synergy when combined with the NEP inhibitor, thiorphan (Wegner (1995) Clin . Exper . Hypert . 17: 861-876).

In another embodiment, the compound of the present invention is administered in combination with a neprilysin (NEP) inhibitor. Representative NEP inhibitors include, but are not limited to: AHU-377; Candoxatril; Candoxatrilat; Dexecadotril ((+) - N- [2 (R) - (acetylthiomethyl) -3-phenylpropionyl] glycine benzyl ester); CGS-24128 (3- [3- (biphenyl-4-yl) -2- (phosphonomethylamino) propionamido] propionic acid); CGS-24592 ( (S) -3- [3- (biphenyl-4-yl) -2- (phosphonomethylamino) propionamido] propionic acid); CGS-25155 (N- [9 (R) -(acetylthiomethyl) -10-oxo-1-azacyclodecane-2 (S) -ylcarbonyl] -4 (R) -hydroxy-L-proline benzyl ester); 3- (1-carbamoylcyclohexyl) propionic acid derivatives described in WO 2006/027680 by Hepworth et al. (Pfizer Inc.); JMV-390-1 (2 (R) -benzyl-3- (N-hydroxycarbamoyl) propionyl-L-isoleucil-L-leucine); Ecadotril; Phosphoramidon; Retro thiorphan; RU-42827 (2- (mercaptomethyl) -N- (4-pyridinyl) benzenepropionamide); RU-44004 (N- (4-morpholinyl) -3-phenyl-2- (sulfanylmethyl) propionamide); SCH-32615 ( (S) -N- [N- (1-carboxy-2-phenylethyl) -L-phenylalanyl] -β-alanine) and its prodrugs SCH-34826 ( (S) -N- [ N- [1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine); Sialorphin; SCH-42495 (N- [2 (S) -(acetylsulfanylmethyl) -3- (2-methylphenyl) propionyl] -L-methionine ethyl ester); Spinorphin; SQ-28132 (N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] leucine); SQ-28603 (N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] -β-alanine); SQ-29072 (7-[[2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] heptanoic acid); Thiorphan and its prodrug racecadotril; UK-69578 (cis-4-[[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid); UK-447,841 (2- {1- [3- (4-chlorophenyl) propylcarbamoyl] -cyclopentylmethyl} -4-methoxybutyric acid); UK-505,749 ( (R) -2-methyl-3- {1- [3- (2-methylbenzothiazol-6-yl) propylcarbamoyl] cyclopentyl} propionic acid); 5-biphenyl-4-yl-4- (3-carboxypropionylamino) -2-methylpentanoic acid and 5-biphenyl-4-yl-4- (3-carboxypropionylamino) -2-methylphene Carbonic acid ethyl ester (WO 2007/056546); Daglutril described in WO 2007/106708 by Khder et al. (Novartis AG) [ (3S, 2'R) -3- {1- [2 '-(ethoxycarbonyl) -4'-phenylbutyl] -cyclopentane-1-carbonylamino} -2,3,4,5- Tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid]; And combinations thereof. In certain embodiments, the NEP inhibitor is AHU-377, candoxartryl, candoxartrillat, GGS-24128, phosphoramidone, SCH-32615, SCH-34826, SQ-28603, thiorphan, and combinations thereof Is selected from. In certain embodiments, the NEP inhibitor is a compound such as daglutril, which also has activity as an inhibitor of both endothelin converting enzyme (ECE) and NEP. Other dual active ECE / NEP compounds may also be used. The NEP inhibitor will be administered in an amount sufficient to provide about 20-800 mg per day, with typical daily dosages ranging from 50-700 mg per day, more generally 100-600 or 100-300 mg per day. Is in.

In one embodiment, the compounds of the present invention are administered in combination with a nitric oxide donor, examples of which include nicorandil; Organic nitrates such as pentaerythritol tetranitrate; And sidnonimines such as linsidomine and molsidomine.

In another embodiment, the compound of the present invention is administered in combination with a nonsteroidal anti-inflammatory agent (NSAID). Representative NSIDs include, but are not limited to: acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, amfenac, ammi Aprilose, amoxiprin, anirolac, apazone, azapropazone, benorilate, benoxaprofen, bezpipepe Bezpiperylon, broperamole, bucloxic acid, carprofen, cardanen, clidanac, diclofenac, diflunisal, diftalone , Enolicam, etodolac, etoricoxib, fenbufen, fenclofenac, fenclozic acid, fenoprofen , Pentiazac, feprazone, flufenamic acid, flufenisal, fluprofen en), flurbiprofen, furofenac, ibufenac, ibuprofen, indomethacin, indoprofen, indoprofen, isoxepac, Isoxycam, ketoprofen, ketoprofen, ketorolac, lofemizole, lornoxicam, meclofenamate, meclofenamic acid ), Mefenamic acid, meloxicam, mesalamine, mesalamine, miroprofen, mofebutazone, nabumetone, napromeen, naproxen, niplum acid ( niflumic acid, oxaprozin, oxpinac, oxyphenbutazone, phenylbutazone, pyroxicam, pirprofen, pranoprofen ( pranoprofen, salsalate, sudoxicam, sulfasalazine, sulindac, suprofen, tenoxicam, But are not limited to, tiopinac, tiaprofenic acid, tioxaprofen, tolfenamic acid, tolmetin, triflumidate, zidometacin, Zomepirac, and combinations thereof. In certain embodiments, the NSAID is selected from etodolak, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxycamp, naproxen, oxaprozin, pyrocampam, and combinations thereof do.

In one embodiment, the compounds of the present invention are administered in combination with an N-methyl d-aspartate (NMDA) receptor antagonist, examples of which are non-limiting examples, amantadine, dextromethorphan ), Dextropropoxyphene, dextropropoxyphene, ketamine, ketobemidone, memantine, methadone, and the like.

In another embodiment, the compounds of the present invention are administered in combination with opioid receptor agonists (also referred to as opioid analgesics). Representative opioid receptor agonists include, but are not limited to: buprenorphine, butorphanol, codeine, dihydrocodeine, fentanyl, hydrocodone, but are not limited to, hydrocodone, hydromorphone, levallorphan, levorphanol, meperidine, methadone, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nalorphine, oxycodone, oxymorphone, pentazocine, propoxyphene, naloxone, naloxone, naloxone, naltrexone, Tramadol, and combinations thereof. In certain embodiments, the opioid receptor agonist is selected from codeine, dihydrocodeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, and combinations thereof.

In one specific embodiment, the compounds of the invention are administered in combination with phosphodiesterase (PDE) inhibitors, in particular PDE-V inhibitors. Representative PDE-V inhibitors include avanafil, lodenafil, mirodenafil, sildenafil (Revatio®), tadalafil (Adcirca®) and vardenafil ( vardenafil) (Levitra®), and udenafil, but are not limited to these.

In another embodiment, the compounds of the present invention are administered in combination with prostaglandin analogs (also referred to as prostanoids or prostacyclin analogs). Representative prostaglandin analogs include, but are not limited to, beraprost sodium, bimatoprost, epoprostenol, iloprost, latanoprost, tafluprost, but are not limited to, bimatoprost, latanoprost, and tafluprost, including, but not limited to, travoprost, treprostinil, and treprostinil.

In another embodiment, a compound of the invention is administered in combination with a prostaglandin receptor agonist, examples of which include, but are not limited to, bimatoprost, latanoprost, travoprost, and the like. It is not limited.

The compounds of the present invention may also be administered in combination with a renin inhibitor, examples of which include aliskiren, enalkiren, remikiren, and combinations thereof , But is not limited thereto.

In another embodiment, the compound of the present invention is administered in combination with a selective serotonin reuptake inhibitor (SSRI). Representative SSRIs include, but are not limited to, citalopram and citalopram metabolites desmethylcitalopram, dapoxetine, escitalopram (e. G. Fluoxetine and fluoxetine desmethyl metabolite norfluoxetine, fluvoxamine (e.g., fluvoxamine maleate), paroxetine (e. G., Escitalopram oxalate) ), Sertraline and the sertraline metabolite demethylsertraline, and combinations thereof.

In one embodiment, the compounds of the present invention are administered in combination with a 5-HT _1D serotonin receptor agonist, examples of which are non-limiting examples, almotriptan, abittriptan, eletriptan triptans such as eletriptan, frovatriptan, naratriptan rizatriptan, sumatriptan, and zolmitriptan.

In one embodiment, the compounds of the present invention are administered in combination with sodium channel blockers, examples of which are non-limiting examples, such as carbamazepine, fosphenytoin, lamotrignine, lidocaine ( lidocaine, mexiletine, oxcarbazepine, phenytoin, and combinations thereof.

In one embodiment, the compounds of the present invention are administered in combination with soluble guanylate cyclase stimulants or activators, examples of which include atasiguat, riociguat, and combinations thereof, This is not restrictive.

In one embodiment, the compounds of the present invention are administered in combination with a tricyclic antidepressant (TCA), examples of which are non-limiting examples, amitriptyline, amitriptylinoxide, butytriptyline (butriptyline), clomipramine, demexiptiline, decipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin , Imipramine, imipraminoxide, lofepramine, melitracen, metapramine, nitroxazephine, nortriptyline ), Noxiptiline, pipeofezine, propizepine, proptriptyline, quinupramine, and combinations thereof.

In one embodiment, a compound of the invention is administered in combination with a vasopressin receptor antagonist, examples of which include, but are not limited to, conivaptan and tolvaptan.

In addition, a combined secondary therapeutic agent may be useful in additional combination therapies including the compounds of the present invention. For example, the compounds of the present invention can be combined with diuretics and ARB, or calcium channel blockers and ARB, or diuretics and ACE inhibitors, or calcium channel blockers and statins. Specific examples include a combination of the ACE inhibitor enalapril (in the maleate salt form) and diuretic hydrochlorothiazide, sold under the trade name Vaseretic®, or the calcium channel blocker amlodipine (in the besylate salt form) and ARB olmesartan (medoxomil Combinations of prodrug forms), or combinations of calcium channel blockers and statins, all of which may be used with the compounds of the present invention. Other therapeutic agents, such as α ₂ -adrenergic receptor agonists and vasopressin receptor antagonists, may also be helpful in combination therapy. Exemplary α ₂ -adrenergic receptor agonists include clonidine, dexmedetomidine, and guanfacine.

The following formulations illustrate representative pharmaceutical compositions of the present invention.

Hard Gelatin Capsules for Exemplary Oral Administration

Compound (50 g) of the invention, 440 g of spray dried lactose and 10 g of magnesium stearate are thoroughly mixed. The resulting composition is then loaded into hard gelatin capsules (500 mg of composition per capsule). Alternatively, the compound of the present invention (20 mg) is thoroughly mixed with starch (89 mg), microcrystalline cellulose (89 mg) and magnesium stearate (2 mg). Thereafter, the mixture was subjected to No. 45 Mesh U.S. Pass through a sieve (No. 45 mesh U.S. sieve) and load into hard gelatin capsules (200 mg of composition per capsule).

Alternatively, the compound of the present invention (30 g), the second agent (20 g), 440 g spray dried lactose and 10 g magnesium stearate are thoroughly mixed and treated as described above.

Exemplary Gelatin Capsule Formulations for Oral Administration

Compounds of the invention (100 mg) are thoroughly mixed with polyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg). The mixture is then loaded into gelatin capsules (400 mg of composition per capsule). Alternatively, the compound of the present invention (70 mg) and the second agent (30 mg) are thoroughly mixed with polyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg) and the resulting mixture is gelatin capsules (400 mg of composition per capsule).

Alternatively, the compound of the present invention (40 mg) is thoroughly mixed with microcrystalline cellulose (Avicel PH 103; 259.2 mg) and magnesium stearate (0.8 mg). The mixture is then loaded into gelatin capsules (Size # 1, white, opaque) (300 mg of composition per capsule).

Tablet Formulations for Exemplary Oral Administration

Compounds of the present invention (10 mg), starch (45 mg), and microcrystalline cellulose (35 mg) were prepared using No. 20 mesh U.S. Pass the sieve and mix thoroughly. Thereby, the resulting granules were dried at 50-60 ° C. and No. 16 mesh U.S. Pass through a sieve. Polyvinylpyrrolidone solution (4 mg as a 10% solution in sterilized water) is mixed with sodium carboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg), and talc (1 mg), and then this mixture No.16 Mesh US Pass through the sieve. Sodium carboxymethyl starch, magnesium stearate and talc are then added to the granules. After mixing, the mixture is compressed in a tablet machine to make a tablet weighing 100 mg.

Alternatively, the compound of the present invention (250 mg) is thoroughly mixed with microcrystalline cellulose (400 mg), dry silicon dioxide fumed (10 mg) and stearic acid (5 mg). The mixture is then compressed to produce tablets (665 mg of composition per tablet).

Alternatively, the compound of the present invention (400 mg) is thoroughly mixed with corn starch (50 mg), croscarmellose sodium (25 mg), lactose (120 mg), and magnesium stearate (5 mg). The mixture is then compressed to produce single-scored tablets (600 mg of composition per tablet).

Alternatively, the compound of the present invention (100 mg) is thoroughly mixed with corn starch (100 mg) with an aqueous gelatin solution (20 mg). The mixture is dried and ground to a fine powder. Microcrystalline cellulose (50 mg) and magnesium stearate (5 mg) are then mixed with the gelatin preparation, granulated and the resulting mixture is compressed to form tablets (100 mg of the compound of the invention per tablet).

Exemplary Oral Suspension Formulations

The following ingredients are mixed to form a suspending agent containing 100 mg of the compound of the present invention per 10 mL of suspension:

ingredient amount The compound of the present invention 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Profile paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum®K (magnesium aluminum silicate) 1.0 g Flavoring 0.035 mL Coloring 0.5 mg Distilled water Sufficient in 100 mL

Illustrative Liquid preparations for oral administration

Suitable liquid formulations are formulations comprising carboxylic acid-based buffers, such as citrate, lactate and maleate buffer solutions. For example, a compound of the invention (which may be premixed with DMSO) may be mixed with 100 mM ammonium citrate buffer and the pH may be adjusted to pH 5, or may be mixed with a 100 mM citric acid solution and the pH may be adjusted to pH 2 have. Such solutions may also include solubilizing excipients, such as cyclodextrins, for example, the solution may comprise 10% by weight hydroxypropyl-β-cyclodextrin.

Other suitable formulations include 5% NaHCO ₃ solution, with or without cyclodextrin.

Injectable Formulations for Exemplary Injection Administration

Compound (0.2 g) of the present invention is mixed with 0.4 M sodium acetate buffer solution (2.0 mL). The pH of the resulting solution is adjusted to pH 4 with 0.5 N aqueous hydrochloric acid solution or 0.5 N aqueous sodium hydroxide solution, if necessary, and then a sufficient volume of water for injection is added to make a total volume of 20 mL. The mixture is then filtered through a sterile filter (0.22 microns) to produce a sterile solution suitable for administration by injection.

Exemplary Inhalation Compositions

Compounds of the invention (0.2 mg) are micronized and blended with lactose (25 mg). This blended mixture is then loaded into a gelatin inhalation cartridge. The contents of the cartridge are administered, for example, using a dry powder inhaler.

Alternatively, the undifferentiated compound (10 mg) of the present invention is dispersed in a solution prepared by dissolving lecithin (0.2 g) in demineralized water (200 mL). The resulting suspension is spray dried and micronized to produce a micronized composition comprising particles having an average diameter of less than about 1.5 μm. The micronized composition then contains pressurized 1,1,1,2-tetrafluoroethane in an amount sufficient to provide from about 10 μg to about 500 μg of the compound of the invention per administration when administered by inhaler Into a metered dose suction cartridge.

Alternatively, compounds of the invention (25 mg) are dissolved in citrate buffered (pH 5) isotonic saline (125 mL). The resulting mixture is stirred and sonicated until the compound is dissolved. The pH of the solution is checked and, if necessary, adjusted to pH 5 by the slow addition of 1N NaOH aqueous solution. The solution is administered using a nebulizer device providing about 10 μg to about 500 μg of the compound of the present invention per dose.

Example

The following preparations and examples are set forth to describe particular embodiments of the invention. However, these particular embodiments are not intended to limit the scope of the invention in any way unless specifically stated otherwise.

The following abbreviations have the following meanings, unless otherwise indicated, and other abbreviations used and not defined herein have their standard, generally accepted meanings:

AcOH acetic acid

(Boc) ₂ O di- t -butyl dicarbonate

(di- t -butyl dicarbonate)

DCC dicyclohexylcarbodiimide

                       (dicyclohexylcarbodiimide)

DCM dichloromethane or

                       Methylene chloride

DIBAL diisobutylaluminum hydride

                       (diisobutylaluminum hydride)

DIPEA N, N -diisopropylethylamine

( N, N -diisopropylethylamine)

DMAP 4-dimethylaminopyridine

DMF N, N - dimethylformamide (N, N -dimethylformamide)

DMSO dimethyl sulfoxide

Dnp 2,4-dinitrophenyl

EDCI N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide

( N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide)

Et ₃ N triethylamine

Et ₂ O diethyl ether

EtOAc < RTI ID = 0.0 > ethyl acetate &

EtOH < RTI ID = 0.0 >

HATU N, N, N ', N' - tetramethyl -O- (7- aza-benzotriazol-1-yl) uronium hexafluorophosphate (N, N, N ', N' -tetramethyl-O- ( 7-azabenzotriazol-1-yl) uronium hexafluorophosphate)

HCTU (2- (6-chloro-1H-benzotriazol-1-yl) -1,1,3,3-tetramethylaluminum hexafluorophosphate) ((2- (6-chloro-1H-benzotriazole- 1-yl) -1,1,3,3-tetramethylaminium hexafluorophosphate))

HEPES 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid

                   (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid)

HOAt 1-hydroxy-7-azabenzotriazole

                       (1-hydroxy-7-azabenzotriazole)

LiHMDS Lithium Hexamethyl Disilazide

                       (lithium hexamethyl disilazide)

Mca (7-methoxycoumarin-4-yl) acyl

                       ((7-methoxycoumarin-4-yl) acyl)

MeCN acetonitrile

MeOH methanol

Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) pallidium (0)

                      (tetrakis (triphenylphosphine) palladium (0))

SilicaCat ^® PP-Pd Silica-based diphenylphosphinepalladium (II) catalyst

               (silica based diphenylphosphine palladium (II) catalyst)

SilicaCat ^® Pd (0) Silica based Palladium (0) Catalyst

                      (silica based palladium (0) catalyst)

TFA Trifluoroacetic acid < RTI ID = 0.0 >

THF tetrahydrofuran

Unless stated otherwise, all materials such as reagents, starting materials and solvents were purchased from commercial sources (such as Sigma-Aldrich, Fluka Riedel-de Haen, etc.) and used without further purification.

The reaction was carried out under a nitrogen atmosphere unless otherwise noted. The progress of the reaction was monitored by thin layer chromatography (TLC), analytical high performance liquid chromatography (analytical HPLC) and mass spectrometry, details of which were specific to the examples. It is detailed in the following. Solvents used for analytical HPLC were as follows: Solvent A was 98% H ₂ O / 2% MeCN /1.0 mL / L TFA; Solvent B was 90% MeCN / 10% H ₂ O / 1.0 mL / L TFA.

The reaction was worked up, for example as specifically described in each preparation example: in general, the reaction mixture was extracted and other purification methods such as temperature dependent crystallization and solvent dependent crystallization, and precipitation Purified. In addition, the reaction mixture was usually purified by preparative HPLC using Microsorb C18 and Microsorb BDS column packings and conventional eluents. The progress of the reaction was generally measured by liquid chromatography mass spectrometry (LCMS). Characterization of isomers was carried out by Nuclear Overhauser effect spectroscopy (NOE). Characterization of the reaction product was typically performed by mass spectrometry and ¹ H-NMR spectroscopy. For NMR measurements, samples are dissolved in deuterated solvents (CD ₃ OD, CDCl ₃ , or DMSO- d ₆ ) and ¹ H-NMR using a Varian Gemini 2000 instrument (400 MHz) under standard observation conditions The spectrum was obtained. Mass spectrometric characterization of the compounds is generally performed using an Applied Biosystems (Foster City, CA) Model API 150 EX instrument or an Agilent (Palo Alto, CA) Model 1200 LC / MSD instrument using the electrospray ionization method (ESMS). It was carried out by.

Production Example 1

Oxodiperoxymolybdenum (pyridine) Hexamethylphosphoric triamide )

Molybdenum oxide (MoO ₃ ; 30 g, 0.2 mol) and 30% hydrogen peroxide (150 mL) were combined with stirring. The reaction vessel was placed in an oil bath equilibrated at 40 ° C. and heated until the internal temperature reached 35 ° C. Thereafter, the heating bath was removed and replaced with a water bath to control the mildly exothermic reaction to maintain the internal temperature at 35-40 ° C. After the initial exotherm time (˜30 min), the reaction vessel was returned to a 40 ° C. oil bath and stirred for a total of 3.5 hours to form a yellow solution with a small amount of suspended white solid. After cooling to 20 ° C., the solution was filtered and the resulting yellow filtrate was cooled to 10 ° C. (cooling with stirring in an ice bath) and hexamethylphosphoric triamide ((Me ₂ N) ₃ PO; HMPA 37.3 g, 0.2 mol) was added dropwise over 5 minutes to form a yellow crystalline precipitate. Stirring was continued for a total of 15 minutes at 10 ° C. and the product was filtered and dry compressed. After 30 minutes in vacuo, the filter cake was combined with MeOH (20 mL) and stirred at 40 ° C. Additional MeOH was added slowly until the solid dissolved. The saturated solution was cooled in a refrigerator to yield a yellow solid (looking like a needle). Breaking the solid mass physically (broken), filtered and washed with cold MeOH (20-30 mL), oxo dipper oxy molybdenum (aq) (hexamethylphosphoric _{triamide) (MoO 5 · H 2 0} · MPA, 46-50 g) was obtained.

MoO ₅ .H ₂ 0 .MPA was shielded from light in a vacuum dryer and dried over phosphorus oxide, yielding a slightly hygroscopic yellow solid, MoO ₅ .HMPA, at 0.2 mm Hg for 24 hours. It was. MoO ₅ HMPA (36.0 g, 0.1 mol) was dissolved in THF (150 mL) and the resulting solution was filtered to remove the precipitate. The filtrate was then stirred at 20 ° C. while dry pyridine (8.0 g, 0.1 mol) was added over 10 minutes. The crystalline, yellow product was collected, washed with dry THF (25 mL) and anhydrous ether (200 mL) and dried in a vacuum drier (1 hour, 0.2 mm Hg) to finely separated yellow solid (36-38 g) ), The title compound, oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) (MoO ₅ Py.HMPA) was obtained.

Production Example 2

(S) -2-biphenyl-4- Yl methyl -5- Oxopyrrolidine -One- Carboxylic acid t - butyl ester

(R) -3-biphenyl-4-yl-2- t -butoxycarbonylaminopropionic acid (50 g, 146.5 mmol), Meldrum's acid (23.3 g, in anhydrous DCM (500 mL), 161.1 mmol) and DMAP (27.8 g, 227 mmol) were added a solution of DCC (33.3 g, 161.1 mmol) in dry DCM (200 mL) under nitrogen at -5 ° C. over 1 h. The resulting mixture was stirred for 8 h at −5 ° C. and then refrigerated overnight during which small crystals of dicyclohexylurea were precipitated. After filtration, the mixture was washed with 5% KHSO ₄ (4 × 200 mL), saturated aqueous NaCl solution (1 × 200 mL) and dried over MgSO ₄ overnight. The resulting solution was evaporated to yield crude compound 1 (68 g) as a pale yellow solid. LC-MS: [M ⁺ Na]: 490, [2M ⁺ Na]: 957.

To a solution of crude Compound 1 (68 g, 146.5 mmol) in anhydrous DCM (1000 mL) was added AcOH (96.8 g, 1.6 mol) at −5 ° C. under nitrogen. The resulting mixture was stirred at −5 ° C. for 0.5 h, then NaBH ₄ (13.9 g, 366 mmol) was added in small portions over 2 h. After stirring at −5 ° C. for one hour, saturated aqueous NaCl solution (300 mL) was added. The organic layer was washed with saturated aqueous NaCl solution (2 × 300 mL), then with water, dried over MgSO ₄ , filtered and evaporated to afford crude Compound 2, chromatography (hexanes: EtOAc = 5: 1 Further purification afforded purified compound 2 (46 g) as a pale yellow solid. LC-MS: [M ⁺ Na]: 476, [2M ⁺ Na]: 929.

A stirred solution of purified Compound 2 (46 g, 101 mmol) in anhydrous toluene (300 mL) was heated and refluxed under nitrogen for 3 hours. After evaporation of the solvent, the residue was purified by chromatography (hexane: EtOAc = 10: 1) to give the title compound (27 g) as a pale yellow solid.

LC-MS: [M ⁺ Na]: 374, [2M ⁺ Na]: 725; 1 H NMR (300 MHz, CDCl ₃ ): δ7.64-7.62 (m, 4H), 7.51-7.46 (m, 2H), 7.42-7.39 (m, 1H), 7.39-7.30 (m, 2H), 4.50- 4.43 (m, 1H), 3.27-3.89 (m, 1H), 2.88-2.80 (m, 1H), 2.48-2.42 (m, 2H), 2.09-1.88 (m, 2H), 1.66 (s, 9H).

Production Example 3

(2R, 4R) -4-amino-5-biphenyl-4-yl-2- Hydroxypentanoic acid  Ethyl ester and (2R, 4S) -4-amino-5-biphenyl-4-yl-2- Hydroxypentanoic acid  Ethyl ester

Step 1: stirred of (S) -2-biphenyl-4-ylmethyl-5-oxopyrrolidine-1-carboxylic acid t -butyl ester (4.4 g, 12.4 mmol) in dry THF (70 mL) To the solution, 1 M LiHMDS solution in THF (28 mL) was added over 15 minutes at -65 ° C. under nitrogen. After stirring at −65 ° C. for 3 hours, oxodiperoxymolybdenum (pyridine) (hexamethylphosphorictriamide) (9 g, 18.6 mmol) was added. The resulting mixture was stirred at −35 ° C. for 2 hours and then saturated Na ₂ S ₂ O ₃ An aqueous solution (60 mL) was added. The organic layer was collected, washed with saturated aqueous NH ₄ Cl solution (60 mL × 3) and saturated aqueous NaCl solution (60 mL × 2), then dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure to afford the crude product. Obtained and further purified by chromatography (hexane: EtOAc = 5: 1) to give compound 1 as a white solid (1.8 g). LC-MS: [2M + Na]: 757.

Step 2: To a solution of compound 1 (1.8 g, 5.0 mmol) in dry DCM (50 mL), DMAP (122 mg, 1 mmol) and Et ₃ N (1.5 g, 14.9 mmol) were added at 0 ° C. under nitrogen. . After stirring 0.5 h at 0 ° C., benzyl chloride (1.0 g, 7.4 mmol) was added over 15 minutes. The resulting mixture was further stirred at 0 ° C. for 2 h, saturated NaHCO ₃ An aqueous solution (50 mL) was added. Collect organic layer, saturated NaHCO ₃ Washed with aqueous solution (50 mL x 2) and saturated aqueous NaCl solution (50 mL x 1), followed by Na ₂ SO ₄ Lt; / RTI > The solids were filtered and the filtrate was concentrated to give crude product and further purified by chromatography (hexanes: EtOAc = 4: 1) to give compound 2A (471 mg) and compound 2B (883 mg) as a white solid. It was. LC-MS: [M + Na]: 494; [2M + Na]: 965.

Compound 2A: ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.02 (m, 2H), 7.57-7.25 (m, 12H), 5.42 (m, 1H), 4.50 (m, 1H), 3.26 -3.21 (m, 1H), 2.90 (m, 1H), 2.58 (m, 1H), 2.15-2.05 (m, 1H), 1.62 (m, 9H)

Compound 2B: ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.06 (m, 2H), 7.58-7.18 (m, 12H), 5.53-5.41 (m, 1H), 4.39 (m, 1H) , 3.57-3.54 (m, 1H), 2.87-2.80 (m, 1H), 2.48-2.44 (m, 1H), 1.98 (m, 1H), 1.63 (m, 9H).

Step 3: To a stirred solution of compound 2A (471 mg, 1 mmol) in anhydrous ethanol (10 mL) was added anhydrous K ₂ CO ₃ (691 mg, 5 mmol) at room temperature under nitrogen. After stirring for 20 hours at room temperature, the solid was filtered off. To the filtrate was added water (30 mL), DCM (30 mL) and saturated aqueous NaCl solution (5 mL). The aqueous layer was separated and extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL), dried over Na ₂ S0 ₄ and concentrated to afford crude product, which was further purified by chromatography (hexanes: EtOAc = 6: 1) to give a white solid. Phosphorus Compound 3 (275 mg) was obtained. LC-MS: [M + Na]: 436, [2M + Na]: 849.

Step 4: Acetyl chloride (685 mg) was added to ethanol (5 mL) at -30 ° C. After stirring at −30 ° C. for 1 hour, a solution of compound 3 (275 mg, 665 μmol) in absolute ethanol (5 mL) was added. The resulting mixture was heated at 25 ° C. and stirred at 25 ° C. for 3 hours. After evaporation of the solvent, the residue was washed with cold anhydrous Et ₂ O (10 mL) to give (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid as a white solid HCl salt. Ethyl ester (207 mg) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 7.99 (m, 3H), 7.66-7.64 (m, 4H), 7.48-7.35 (m, 5H), 6.08 (m, 1H), 4.21 ( m, 1H), 4.09-4.05 (m, 2H), 3.52 (m, 1H), 2.97-2.95 (m, 2H), 1.89-1.87 (m, 2H), 1.19-1.14 (m, 3H).

Step 5: To a stirred solution of compound 2B (883 mg, 1.9 mmol) in anhydrous ethanol (15 mL) was added anhydrous K ₂ CO ₃ (1293 mg, 9.4 mmol) at room temperature under nitrogen. After stirring for 20 hours at room temperature, the solid was filtered off. To the filtrate was added water (30 mL), DCM (30 mL) and saturated aqueous NaCl solution (5 mL). The aqueous layer was separated and extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL), dried over Na ₂ SO ₄ and concentrated to afford crude product, which was further purified by chromatography (hexanes: EtOAc = 6: 1) to give a white solid. Phosphorus Compound 4 (524 mg) was obtained. LC-MS: [M + Na]: 436, [2M + Na]: 849.

Step 6: To ethanol (8 mL) at -30 ° C., acetyl chloride (1300 mg) was added. After stirring at −30 ° C. for 1 hour, a solution of compound 4 (524 mg, 1.3 mmol) in absolute ethanol (8 mL) was added. The mixture was heated at 25 ° C. and stirred at 25 ° C. for 3 hours. After evaporation of the solvent, the residue is washed with cold anhydrous Et ₂ O (10 mL) to give (2R, 4S) -4-amino-5-biphenyl-4-yl-2-hydroxyphen, a white solid HCl salt. Carbonic ethyl ester (395 mg) was obtained. LC-MS: [M + H]: 314, [2M + Na]: 649.

¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.14 (m, 3H), 7.66-7.62 (m, 4H), 7.47-7.31 (m, 5H), 5.87-5.85 (m, 1H), 4.34 (m, 1H), 4.08-4.00 (m, 2H), 3.48 (m, 1H), 3.09 (m, 1H), 2.85-2.81 (m, 1H), 1.88 (m, 1H), 1.76 (m, 1H), 1.15-1.10 (m, 3H).

(2R, 4R) -4-amino-5-biphenyl-4-yl-2- Hydroxypentanoic acid  Alternative Synthesis of Ethyl Ester

[ (S) -2-biphenyl-4-yl-1- (2,2-dimethyl-4,6-dioxo- [1,3] dioxan-5-ylmethyl) in anhydrous toluene (1 L) A solution of ethyl] -carbamic acid t -butyl ester (143 g, 320 mmol) was heated and refluxed under nitrogen overnight. The solvent was removed under reduced pressure to give (S) -2-biphenyl-4-ylmethyl-5-oxopyrrolidine-1-carboxylic acid t -butyl ester, which was used directly without further purification, EtOAc To a solution of 3N HCl in (1.2 L). The resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo. The residue was recrystallized in EtOAc (300 mL) to give a first batch of deprotected compound (56 g). A mother liquid was applied to the chromatography column (eluted with 1: 1 EtOAc and hexanes to 100% EtOAc) to give a second batch of deprotected compound (8 g). To a suspension of deprotected compound (64 g, 250 mmol) in anhydrous THF (500 mL), BuLi (2.5 M in 100 mL of hexane, 2.5 M) was added dropwise. After stirring for 0.5 h, pivaloyl chloride (34 g, 0.28 mol) was added dropwise. The mixture was stirred at -78 < 0 > C for 1 hour. The reaction was then quenched with saturated aqueous NH ₄ Cl solution and the compound obtained was quenched with a mixture extracted with EtOAc. The extract was dried over MgSO ₄ and concentrated to give (S) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) pyrrolidin-2-one (85 g) as a white solid. Obtained.

(S) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) pyrrolidin-2-one (40 g, 120 mmol) was dissolved in anhydrous THF (400 mL), Stir at -78 ° C under nitrogen. To this was added 1.5 eq of a 2.0 M THF solution of sodium bis (trimethylsilyl) amide over 5 minutes. The pale yellow mixture was stirred under nitrogen at −78 ° C. for 20 minutes and slowly dropwise oxaziridine (53 g, 180 mmol) with a 200 mL solution in THF. The resulting mixture was stirred for 0.5 h. The reaction was quenched with saturated aqueous NH ₄ Cl solution and the resulting mixture was quenched with a mixture extracted with EtOAc (1 L). The extract was washed with 1N HCl (1 L), dried over MgSO ₄ and concentrated to 500 mL volume. The precipitated white solid was filtered off and the filtrate was concentrated after addition of silica gel (200 g) to remove the solvent. The residue was loaded onto a column of silica gel (900 g) (8x80 cm), prefilled in hexane. Elution was initially performed with DCM: hexane (1: 1). Once oxaziridine and imine were collected completely, the column was eluted with DCM to give (3R, 5R) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) -3 as a yellow oil. -Hydroxypyrrolidin-2-one (21 g, 98% purity) was obtained.

(3R, 5R) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) -3-hydroxypyrrolidin-2-one (56 g, 0.156 mol) was converted to ethanol (700 mL) and 12N HCl (700 mL). The resulting mixture was heated to 90-95 ° C. for 20 hours. The resulting mixture was concentrated in an 80 ° C. water bath under reduced pressure. Ethanol (100 mL) was added to the residue and the resulting mixture was filtered to give a yellow solid. This solid was suspended in 3N HCl / ethanol (800 mL). The resulting mixture was refluxed for 3 hours. The resulting solution was concentrated to reduced volume (˜200 mL volume) and ether (200 mL) was added. The resulting pale yellow solid was filtered and dried under reduced pressure to give (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (43 g).

Production Example 4

(2R, 4R) -4-amino-5-biphenyl-4-yl-2- Hydroxypentanoic acid  Butyl ester

1-butanol (40 mL, 400 mmol) was cooled in an ice bath and acetyl chloride was added dropwise until 4N HCl concentration was reached. The resulting mixture was allowed to warm up to room temperature. (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 250 mg, 710 μmol) is added to acidified butanol (15 mL) and obtained The resulting mixture was capped and heated to 80 ° C. for 3 h. The resulting product was dried under vacuum to afford the title compound (220 mg) as a white / orange flaky solid HCl salt.

Example 1

A. (2R, 4R) -4-[(5-acetyl-2H- pyrazole- 3-carbonyl) amino] -5-biphenyl-4-yl-2 -hydroxypentanoic acid ethyl ester ( R ⁷ = - CH ₂ CH ₃₎

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 500 mg, 1 mmol, 1.0 eq.), 5-acetyl-2H-pyrazole 3-carboxylic acid (330.4 mg, 2.1 mmol, 1.5 eq.), And HATU (820 mg, 2.1 mmol, 1.5 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (750 μl) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and the product was purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA) to give the title compound (300 mg) as a TFA salt. , Purity 98%) was obtained. MS m / z [M + H] ⁺ for C ₂₅ H ₂₇ N ₃ O ₅ , calculated 450.20; Measured value 450.2.

B. (2R, 4R) -4-[(5-acetyl-2H- pyrazole- 3-carbonyl) amino] -5-biphenyl-4-yl-2 -hydroxypentanoic acid ( R ⁷ = H)

A portion (200 mg) of purified ethyl ester (Compound A) was dissolved in ethanol (˜10 mL) and the solution was made basic (˜200 μL) by addition of 10N NaOH. The resulting mixture was monitored over 1 hour until the final deprotection was complete. The mixture was acidified with equal volume (˜200 μl) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound (160 mg; purity 100%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₃ H ₂₃ N ₃ O ₅ , calculated 422.16; Found 422.2.

C. (2R, 4R) -4-[(5-acetyl-2H- pyrazole- 3-carbonyl) amino] -5-biphenyl-4-yl-2 -hydroxypentanoic acid butyl ester ( R ⁷ = -( CH ₂ ) ₃ CH ₃ )

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester (HCl salt; 500 mg, 1 mmol, 1.0 eq.), 3-acetyl-1H-pyrazole -5-carboxylic acid (330.4 mg, 2.1 mmol, 1.5 eq.), And HATU (820 mg, 2.1 mmol, 1.5 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (750 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and the product was purified using reverse phase chromatography to give the title compound (45 mg; purity 95%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₇ H ₃₁ N ₃ O ₅ , calculated 478.23; Found 478.4.

D. (2R, 4R) -4-[(5-acetyl-2H- pyrazole- 3-carbonyl) amino] -5-biphenyl-4-yl-2 -hydroxypentanoic acid 2 -methoxyethyl ester ( R ⁷ =-( CH ₂ ) ₂ OCH ₃ )

A saturated HCl solution in 2-methoxyethanol was prepared by dropping acetyl chloride (˜400 μL) dropwise into 10 mL of anhydrous alcohol. To this solution, (2R, 4R) -4-[(5-acetyl-2H-pyrazol-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (21.3 mg, 47.4 μmol) was added and the resulting mixture was heated to 60 ° C. for 1-2 h. The material obtained was dried under vacuum. The product was then purified using reverse phase chromatography to afford the title compound (10 mg; purity 100%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₆ H ₂₉ N ₃ O ₆ , calculated 480.21; Found 480.4.

E. (2R, 4R) -4 - [(5- acetyl -2H- pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid Hi de 5-methyl-2 -Oxo- [1,3] dioxol -4- ylmethyl ester ( R ⁷ = -CH ₂ -5- methyl- [1,3] dioxol-2-one)

(2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid (20 mg, 50 μmol) It was dissolved in dry DMF (2 mL). Dicesium carbonate (50 mg, 0.2 mmol) was added and the resulting mixture was stirred at 0 ° C. for one hour. 4-chloromethyl-5-methyl-1, 3-dioxol-2-one (20 mg, 0.1 mmol) was added and the resulting mixture was stirred at rt overnight. EtOAc (20 mL) was added and the resulting mixture was washed with saturated aqueous NaCl solution (100 mL) and dried under vacuum. The material obtained was purified using reverse phase chromatography to give the title compound (5 mg, purity 100%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₈ H ₂₇ N ₃ O ₈ , calculated 534.18. Found 534.4.

F. (2R, 4R) -4 - [(5- acetyl -2H- pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid 2-morpholin-de Hi - 4-yl-ethyl ester ( R ⁷ =-( CH ₂ ) ₂ -morpholine)

(2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid (50 mg, 120 μmol, 1.1 eq.) and HATU (42 mg, 110 μmol, 1.0 eq.) were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. 4-morpholineethanol (73 mg, 560 μmol, 5.0 eq.) Was added followed by DIPEA. The resulting mixture was stirred for 1 hour and then the material obtained was dried under vacuum. The product was then purified using reverse phase chromatography to afford the title compound (approximately 4 mg, purity 95%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₉ H ₃₄ N ₄ O ₆ , calculated 535.25. Measured value 535.4.

G. (2R, 4R) -4-[(5-acetyl-2H- pyrazole- 3-carbonyl) amino] -5-biphenyl-4-yl-2 -hydroxypentanoic acid 2- methanesulfonylethyl Ester ( R ⁷ =-( CH ₂ ) ₂ - SO ₂ - CH ₃ )

2- (methylsulfonyl) ethanol (690 mg, 5.6 mmol) was warmed to 40 ° C. and 0.5 equivalent of acetyl chloride was added with stirring for 5 minutes. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (50 mg, 110 μmol ) Was added, the reaction vessel was capped and heated to 70 ° C. for 2 hours. The product was then purified using reverse phase chromatography to give the title compound (approximately 28 mg, purity 95%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₆ H ₂₉ N ₃ O ₇ S, calculated 528.17; Found 528.4.

Production Example 5

Acetoxy (diethoxyphosphoryl) acetic acid ethyl ester

Ethyl 2-oxoacetate (50%) (74 g, 724.8 mmol, 1.0 eq.) Was added to a solution of diethyl hydrogen phosphite (50 g, 362.1 mmol, 1.0 eq.) In toluene (100 mL). Was added dropwise with stirring at 0 ° C. under nitrogen. Et ₃ N (110 g, 1.1 mol, 3.0 eq.) Was added dropwise with stirring at 0 ° C. The resulting solution was stirred at rt for 1 h. Acetic anhydride (37 g, 362.4 mmol, 1.0 eq.) Was added dropwise with stirring to the obtained mixture at 0 ° C. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 with 2N HCl. The resulting solution was extracted with DCM (3 × 150 mL) and the organic layers combined, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was loaded on a silica gel column and eluted with EtOAc: hexanes (1: 2-1: 5) to give the title compound (52 g) as a pale yellow liquid.

Production Example 6

[ (R) -2-biphenyl-4-yl-1- ( Methoxymethylcarbamoyl )ethyl] Carbamic acid t - butyl ester

Step 1: N - t- Boc-D-tyrosine (80.0 g, 284.4 mmol, 1.0 eq.), O, N -dimethyl-hydroxylamine hydrochloride (33.3 g, 341.4 mmol, 1.2 eq.), 1-ethyl -3-((3-dimethylamino) -propyl) carbodiimide hydrochloride (81.8 g, 426.7 mmol, 1.5 eq.), Hydroxybenzotriazole (57.6 g, 426.4 mmol, 1.5 eq.), And DCM ( Dried (800 mL) was combined with stirring under nitrogen. The resulting mixture was cooled to 0 ° C. and Et ₃ N (44.0 g, 434.8 mmol, 1.53 eq.) Was added dropwise over 40 minutes with stirring. The resulting mixture was stirred at rt overnight, then washed with saturated aqueous NaHCO ₃ (2 × 300 mL). The organic layer was separated and the aqueous layer was reextracted with DCM (200 mL). The organic phases were combined, dried over Na ₂ SO ₄ and concentrated in vacuo to yield crude Compound 1 (100 g) as a yellow solid.

Step 2: Compound 1 (100.0 g, crude, 308.3 mmol, 1.0 eq.), Pyridine (61.0 g, 771.2 mmol, 2.5 eq.), And DCM (dry) (1000 mL) were combined with stirring under nitrogen. The resulting mixture was cooled to −20 ° C. and then trifluoromethanesulfonic anhydride (104.0 g, 368.6 mmol, 1.2 eq.) Was added dropwise with stirring at −20 ° C. over 30 minutes. The resulting solution was then stirred at -20--15 ° C for 30 minutes. The reaction was then quenched by addition of water (250 mL). The resulting mixture was washed with 0.5N NaOH solution (2x300 mL) and 15% citric acid solution (2x300 mL). The basic aqueous layer was reextracted with DCM (200 mL) and the organic phases combined, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was loaded on a silica gel column and eluted with EtOAc: hexanes (0-1: 5) to give compound 2 (97.7 g) as a pale-yellow oil.

Step 3: Phenylboronic acid (53.0 g, 434.7 mmol, 2.03 eq.), Potassium carbonate (45.0 g, 325.6 mmol, 1.52 eq.), Tetrakis (triphenylphosphine) palladium (0) (12.5 g, 10.8 mmol , 0.05 eq.), And toluene (distilled) (800 mL) were combined with stirring under nitrogen. Before adding 200 mL of the toluene solution of compound 2 (97.7 g, 214.1 mmol, 1.0 eq.), The resulting suspension was degassed and heated to 80 ° C. The thick suspension was stirred at 80 ° C. overnight. The reaction process was monitored by LCMS, indicating an incomplete reaction. After recovering the crude product / starter mixture by chromatography, additional phenylboronic acid (21.2 g), potassium carbonate (18.0 g), tetrakis (triphenylphosphine) palladium (0) (5.0 g) were added and The resulting mixture was suspended in toluene (distilled) (700 mL). The resulting mixture was heated to 80 ° C. and stirred overnight. Upon completion, the reaction was quenched by addition of water (300 mL). The resulting mixture was extracted with EtOAc (2x300 mL) and the organic layers combined. The organic phase was washed with saturated aqueous NaCl solution (1 × 300 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was loaded on a silica gel column and eluted with EtOAc: hexanes (0-1: 3) to afford the title compound (50.0 g) as a white solid.

Production Example 7

( (R) -2-biphenyl-4-yl-1- Formylethyl ) Carbamic acid t - butyl ester

[ (R) -2-biphenyl-4-yl-1- (methoxymethylcarbamoyl) ethyl] carbamic acid t -butyl ester (7.5 g, 19.5 mmol, 1.0 eq.) Was distilled under THF (nitrogen) ) (100 mL). Lithium aluminum hydride (750 mg, 19.8 mmol, 1.0 eq.) Was added to the stirred solution resulting in several batches at −5˜0 ° C. over a period of 30 minutes. The resulting solution was stirred at -5-0 ° C for 30 minutes. Then a solution of KHSO ₄ (6.6 g) in water (35 mL) was added to quench the reaction. The resulting solution was combined with 1N HCl (75 mL) solution and stirred for 5 minutes. EtOAc (100 mL) was added and the resulting solution was extracted with EtOAc (3 × 100 mL) and the organic layers combined to give the title compound (6.3 g) as a yellow oil.

Production Example 8

(R) -4-amino-5-biphenyl-4-yl-2- Hydroxypentanoic acid  Ethyl ester

Step 1: A solution of acetoxy (diethoxyphosphoryl) acetic acid ethyl ester (15.6 g, 55.3 mmol, 1.2 equiv) in THF (dry) (150 mL) was cooled under nitrogen to -78 ° C. LiHMDS (1M in THF) (55.3 mL, 1.2 eq.) Was added dropwise with stirring at -78 ° C. After stirring for 30 min at that temperature, ( (R) -2-biphenyl-4-yl-1-formylethyl) carbamic acid t -butyl ester (15.0 g, crude) in THF (dry) (30 mL) , 1.0 eq.) Solution was added dropwise over 15 minutes. Stirring was continued at −78 ° C. for 1.5 h before pouring the resulting mixture into a cold solution containing water (200 mL) and EtOAc (200 mL). The organic layer was separated repeatedly and the aqueous layer was reextracted with EtOAc (2x100 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated and the residue was purified by flash chromatography (EtOAc / hexane = 0-1: 10) to give compound 1 (10.5 g) as a white solid. .

Step 2: A stirred solution of compound 1 (10.5 g, 23.2 mmol, 1.0 eq.) In ethanol (anhydrous) (100 mL) was combined with palladium carbon (1.0 g) under nitrogen. The resulting mixture was purged four times with hydrogen, and then hydrogen was bubbled over two hours at room temperature. Palladium carbon was removed by filtration and the filtrate was concentrated in vacuo to yield crude Compound 2 (10.0 g), a pale yellow oil which was used without further purification.

Step 3: Compound 2 (10.0 g, 22.0 mmol, 1.0 eq.) In ethanol (anhydrous) (100 mL) with potassium carbonate (6.1 g, 44.1 mmol, 2.0 eq.) And the resulting solution at room temperature for 2 hours Was stirred. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was loaded on a silica gel column (EtOAc / hexane = 0-1: 5) to give compound 3 (6.0 g) as a white solid.

Step 4: Compound 3 (6.0 g, 14.5 mmol, 1.0 eq.) Was dissolved in DCM (dry) (120 mL) and HCl was bubbled into the mixture obtained over 5-6 hours at room temperature. Solid precipitate was observed. The mixture was concentrated to half volume and filtered. The solid was collected, washed with cold EtOAc and dried under reduced pressure to give the title compound (4.2 g) as an off-white solid HCl salt. LC-MS (ES, m / z ): 314 [M-HCl + H] < ⁺ >.

^{1 H NMR (300 MHz, DMSO} ): δ (ppm) = 8.07 (s, 1.9H), 7.96 (s, 1.2H), 7.65-7.69 (m, 4.0H), 7.45-7.5 0 (m, 2.0H ), 7.33-7.39 (m, 3.0H), 6.05-6.07 (m, 0.63H), 5.88-5.90 (m, 0.88H), 4.32-4.38 (m, 0.80H), 4.18-4.31 2H), 3.50 (s, 1H), 2.75-3.05 (m, 2H), 1.83-1.94 (m, 1H), 1.71-1.82 m, 3.3H).

Example 2

A. 5- ((1R, 3S) -1- biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxy-propyl carbamoyl) -2H- pyrazole-3-carboxylic acid (R ⁷ = -CH ₂ CH ₃ )

B. 5- ((1R, 3R) -1- biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxy-propyl carbamoyl) -2H- pyrazole-3-carboxylic acid (R ⁷ = -CH ₂ CH ₃ )

C. 5-( (1R, 3S) -1-biphenyl-4- ylmethyl- 3- carboxy- 3 -hydroxypropylcarbamoyl ) -2H-pyrazole-3 -carboxylic acid ( R ⁷ = H )

D. 5-(( 1R, 3R) -1-biphenyl-4- ylmethyl- 3- carboxy- 3 -hydroxypropylcarbamoyl ) -2H-pyrazole-3 -carboxylic acid (D; R ⁷ = H)

(R) 4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (500 mg, 1.6 mmol, 1.0 eq.), 3,5-pyrazoledicarboxylic acid (250 mg , 1.6 mmol, 1.6 eq.), And HATU (610 mg, 1.6 mmol, 1.0 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (1 mL) was added and the mixture was stirred for 1 hour. The resulting mixture was dried under vacuum and the product was purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA) to give 5-( (R) -as the TFA salt. 1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxypropylcarbamoyl) -2H-pyrazole-3-carboxylic acid was obtained.

The material obtained was separated by preparative HPLC, purified using reverse phase chromatography and dried in vacuo to yield compounds A and B as TFA salts. Compounds A and B were each dissolved in ethanol (˜100 mL) and 10N NaOH was added to make the solution basic (˜200 μl). Each mixture was monitored over 1 hour until the final deprotection was complete. Each mixture was acidified with equal volume (˜200 μl) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to determine compound C (52 mg; purity 100%; MS m / z [M + H] ⁺ for C ₂₂ H ₂₁ N ₃ O ₆ , calculated 424.14; Value 424.2) and compound D (65 mg; purity 100%; MS m / z [M + H] ⁺ , calculated 424.14; measured 424.2) for C ₂₂ H ₂₁ N ₃ O ₆ .

E. 5-( (1R, 3R) -1-Biphenyl-4- ylmethyl- 3 -butoxycarbonyl- 3-hydroxy- propylcarbamoyl ) -1H- pyrazole- 3 -carboxylic acid ( R ⁷ =-( CH ₂ ) ₃ CH ₃ )

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester (HCl salt; 108 mg, 286 μmmol, 1.0 eq.), 3,5-pyrazoldicar Acids (66.9 mg, 429 μmol, 1.5 eq.), And HATU (160 mg, 430 μmol, 1.5 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (150 μl) was added and the resulting mixture was stirred for 1 hour. The mixture was dried under vacuum and the product was purified using reverse phase chromatography to give the title compound (60 mg; purity 98%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₆ H ₂₉ N ₃ O ₆ , calculated 480.21; Found 480.4.

Example 3

A. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2 -methoxyethyl ) methylcarbamoyl ] -2H- pyrazole- 3-car Carbonyl} amino) pentanoic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2 -methoxyethyl ) methylcarbamoyl ] -2H- pyrazole- 3-carb Carbonyl} amino) pentanoic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

C. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2 -methoxyethyl ) methylcarbamoyl ] -2H- pyrazole- 3-car Carbonyl} amino) pentanoic acid ( R ⁷ = H)

D. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2 -methoxyethyl ) methylcarbamoyl ] -2H-pyrazole-3-car Carbonyl} amino) pentanoic acid ( R ⁷ = H)

(R) 4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (900 mg, 3.0 mmol, 1.0 eq.), 3,5-pyrazoledicarboxylic acid (448 mg , 2.9 mmol, 1.0 eq.), N- (2-methoxyethyl) methylamine (256 mg, 2.9 mmol, 1.0 eq.), And HATU (1090 mg, 2.9 mmol, 1.0 eq.) In DMF (5 mL ) And the resulting mixture was stirred for 2 minutes. DIPEA (1 mL) was added and the mixture was stirred for 1 hour. The mixture is dried under vacuum and the product is purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA) to (R) -5-biphenyl- as a TFA salt. 4-yl-2-hydroxy-4-({5-[(2-methoxyethyl) methylcarbamoyl] -2H-pyrazole-3-carbonyl} amino) -pentanoic acid ethyl ester (25 mg) Obtained.

This material was separated by preparative HPLC, purified using reverse phase chromatography and dried in vacuo to afford compounds A and B, which are TFA salts. Compounds A and B were each dissolved in ethanol (˜10 mL) and 10N NaOH was added to make the obtained solution (˜200 μl) basic. Each mixture was monitored over 1 hour until the final deprotection was complete. Each mixture was acidified with equal volume (˜200 μl) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give Compound C (20.6 mg; purity 100%; MS m / z [M + H] ⁺ for C ₂₆ H ₃₀ N ₄ O ₆ , calculated 495.22; determined by TFA salt; Value 495.22) and D (8.3 mg; purity 100%; MS m / z [M + H] ⁺ , calculated 495.22; measured 495.22) for C ₂₆ H ₃₀ N ₄ O ₆ .

Example 4

A. (2R, 4R) -4-{[5- ( azetidine -1-carbonyl) -2H- pyrazole- 3-carbonyl] amino} -5-biphenyl-4-yl - 2 -hydroxy Pentanoic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 100 mg, 286 μmol, 1.0 eq.), 3,5-pyrazoldicar Acids (66.9 mg, 429 μmol, 1.5 eq.), And HATU (160 mg, 430 μmol, 1.5 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (150 μL) was added and the mixture was stirred for 1 hour. Azetidine hydrochloride (40.0 mg, 429 μmol, 1.5 eq.) Was added together with a second equivalent of HATU and the resulting mixture was briefly stirred. Additional DIPEA (2.0 eq.) Was added and the mixture was stirred. The mixture was dried under vacuum and purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA) to give the title compound (20 mg; purity 95%) as a TFA salt. Obtained. MS m / z [M + H] ⁺ for C ₂₇ H ₃₀ N ₄ O ₅ , calculated 491.22. Found 491.4.

B. (2R, 4R) -4-{[5- ( azetidine -1-carbonyl) -2H- pyrazole- 3-carbonyl] amino} -5-biphenyl-4-yl-2-hydroxy - pentanoic acid (R ⁷ = H)

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 50 mg, 0.1 mmol, 1.0 eq.), 3,5-pyrazoldicar Acid monohydrate (29.9 mg, 173 μmol, 1.2 eq.), And HATU (82 mg, 210 μmol, 1.5 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (75 μL) was added and the resulting mixture was stirred for 1 hour. Azetidine hydrochloride (20.0 mg, 214 μmol, 1.5 eq.) Was added with a second equivalent of HATU and the resulting mixture was briefly stirred. The mixture was dried under vacuum to give crude ester. The crude ester was dissolved in ethanol (˜10 mL) and 10N NaOH was added to make the solution (˜200 μL) basic. The resulting mixture was monitored over 1 hour until the final deprotection was complete. The mixture was acidified with equal volume (˜200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound (17 mg; purity 95%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₅ H ₂₆ N ₄ O ₅ , calculated 463.19; Found 463.4.

Example 5

A. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- ( pyrrolidine- 1-carbonyl) -2H- pyrazole- 3-carbonyl] amino } Pentanic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 85 mg, 240 μmol, 1.0 eq.), 3,5-pyrazoldicar Acid monohydrate (40 mg, 0.2 mmol, 1.0 eq.), And HATU (90 mg, 0.2 mmol, 1.0 eq.) Are combined in DMF (5 mL) and the resulting mixture is stirred for 2 minutes. DIPEA (150 μl) was added and the resulting mixture was stirred for 1 hour. A second equivalent HATU was added followed by pyrrolidin (20.3 μl, 243 μmol, 1.0 eq.) (1N in THF) and a second equivalent of DIPEA. Upon completion of the reaction, the mixture was dried under vacuum and purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA) to give the title compound (65) as a TFA salt. mg; purity 98%) was obtained. MS m / z [M + H] ⁺ for C ₂₈ H ₃₂ N ₄ O ₅ , calculated 505.24; Found 505.4.

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- ( pyrrolidine- 1-carbonyl) -2H- pyrazole- 3-carbonyl]- Amino} pentanic acid ( R ⁷ = H)

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 50 mg, 0.1 mmol, 1.0 eq.), 3,5-pyrazoldicar Acid monohydrate (20.0 mg, 0.1 mmol, 1.0 eq.), And HATU (50 mg, 0.1 mmol, 1.0 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA (75 μL) was added and the mixture was stirred for 1 hour. A second equivalent of HATU was added followed by pyrrolidine (20.0 mg, 280 μmol, 2.0 eq.) And a second equivalent of DIPEA. The resulting mixture was dried under vacuum to afford crude ester. The crude ester was dissolved in ethanol (˜10 mL) and 10N NaOH was added to make the resulting solution (˜200 μL) basic. The resulting mixture was monitored over 1 hour until the final deprotection was complete. The mixture was acidified with equal volume (˜200 μl) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound (25 mg; purity 95%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₆ H ₂₈ N ₄ O ₅ , calculated 477.21; Found 477.0.

Example 6

A. (2R, 4R ) -5-biphenyl-4-yl-2-hydroxy-4-[(2 -hydroxypyrimidine- 5-carbonyl) amino] pentanoic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(2 -hydroxypyrimidine- 5-carbonyl) amino] pentanoic acid ( R ⁷ = H)

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 200 mg, 572 μmol, 1.0 eq.) And 2-hydroxypyrimidine-5 -Carboxylic acid (88.1 mg, 629 μmol) was suspended in DMF (5.0 mL). HATU (239 mg, 629 μmol) was added followed by DIPEA (299 μl) and the resulting mixture was stirred at rt until the reaction was complete (˜2 h). The mixture was divided into two equal portions and the two solutions were concentrated. One portion was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give Compound A (59.2 mg) as a TFA salt. MS m / z [M + H] ⁺ calc'd for C ₂₄ H ₂₅ N ₃ O ₅ , 436.18. 436.4 Measurements. The remaining portion was dissolved in THF (2.0 mL). LiOH monohydrate (120 mg, 2.9 mmol) in water ((2.0 mL) was added and the mixture was stirred for ˜ 1 h. The reaction was quenched with AcOH addition and the solution was concentrated. Purification by preparative HPLC (10-70% MeCN / H ₂ O) gave TFA salt Compound B (27.8 mg) MS m / z [M + H] ⁺ for C ₂₂ H ₂₁ N ₃ O ₅ . Calculated 408.15; measured 408.4.

Example 7

A. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(3 -hydroxyisoxazole- 5-carbonyl) amino] pentanoic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

3-hydroxyisoxazole-5-carboxylic acid (81.2 mg, 629 μmol, 1.1 eq.) Was dissolved in DMF (5.0 mL). DIPEA (299 μl) and HOAt (85.6 mg, 629 μmol, 1.1 eq.) Were added followed by EDCI (111 μl, 1.1 eq.). The resulting solution was stirred for 5 minutes. Then (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 200 mg, 572 μmol, 1.0 eq.) Was added and the resulting mixture Was stirred at rt overnight. The mixture was concentrated and the crude product was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give the title compound (50.8 mg, 98% purity) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₃ H ₂₄ N ₂ O ₆ , calculated 425.16. Found 425.4.

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3 -hydroxyisoxazole- 5-carbonyl) amino] pentanoic acid ( R ⁷ = H)

(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 200 mg, 572 μmol, 1.0 eq.) And 3-hydroxyisoxazole-5 -Carboxylic acid (81.2 mg, 629 μmol) was suspended in DMF (5.0 mL). HATU (239 mg, 629 μmol) was added followed by DIPEA (299 μl) and the resulting mixture was stirred at rt overnight. The mixture was concentrated and the crude compound was used without purification. The crude material was dissolved in THF (3.0 mL). LiOH monohydrate (240 mg, 5.7 mmol) in water (3.0 mL) was added and the mixture was stirred at rt for 1 h. The mixture was concentrated and the crude product was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give the title compound (36.6 mg, 97% purity) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₁ H ₂₀ N ₂ O ₆ , calculated 397.13. Found 397.2.

C. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3 -hydroxyisoxazole- 5-carbonyl) amino] pentanoic acid 5- methyl -2-oxo- [1,3] dioxol -4- ylmethyl ester ( R ⁷ = -CH ₂ -5- methyl- [1,3] dioxol-2-one)

(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxy-pentanoic acid ethyl ester; Hydrochloride (1.6 g, 4.6 mmol, 1.0 eq.) Was dissolved in DCM (100 mL) and cooled to 0 ° C. Di- t -butyldicarbonate (1.2 g, 5.4 mmol, 1.2 eq.) Was added as a solid, followed by DIPEA (1.6 mL, 9.1 mmol). The resulting mixture was stirred at rt overnight. The product was purified by flash chromatography (0-75% EtOAc / hexanes) and then dissolved in ethanol and sufficient equivalent of 10N NaOH was added to make the obtained solution basic (pH = 14). The reaction was monitored until deprotection was complete (˜1 hour). EtOAc (200 mL) was added and the mixture was washed with 1N HCl (100 mL), followed by saturated aqueous NaCl solution (100 mL). The organic layer was left, dried over anhydrous MgSO ₄ for 10 minutes, filtered and evacuated to dryness to give (2R, 4R) -5-biphenyl-4-yl-4- t -butoxycar Bonylamino-2-hydroxypentanoic acid (1.2 g) was obtained.

(2R, 4R) -5-Biphenyl-4-yl-4- t -butoxycarbonylamino-2-hydroxypentanoic acid (500 mg, 1.0 mmol, 1.0 eq.) In dry DMF (10.0 mL) Dissolved. The resulting solution was cooled to 0 ° C. and dicesium carbonate (465 mg, 1.4 mmol, 1.1 eq.) Was added. The mixture was stirred for 30 minutes and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.1 eq.) Was added. The resulting mixture was stirred for additional 1 hour at 0 ° C. and then warmed to room temperature with stirring. The mixture was stirred further overnight. EtOAc (20 mL) was added, followed by washing with saturated aqueous NaCl solution (100 mL). The product was dried under vacuum and purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA), (2R, 4R) -5-biphenyl-4-yl 4- t -butoxycarbonylamino-2-hydroxypentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester was obtained. This material was dissolved in 4N HCL in dioxane and stirred at room temperature for 2 hours. The material was dried under vacuum and then azeotroped with toluene to give (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2- Oxo- [1,3] dioxol-4-ylmethyl ester was obtained and used in the next step without further purification.

(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester (100 mg, 0.3 mmol, 1.0 eq.) And 3-hydroxyisoxazole-5-carboxylic acid (50.5 mg, 391 μmol, 1.5 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA was added and the resulting mixture was stirred for 1 hour. The material obtained was dried under vacuum and purified using reverse phase chromatography to yield the title compound (40 mg, 98% purity). MS m / z [M + H] ⁺ for C ₂₆ H ₂₄ N ₂ O ₉ , calculated 509.15; Found 509.4.

Example 8

A. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (1-hydroxy- 1- methylethyl ) -1 H - pyrazole-3-carbonyl] Amino} pentanic acid ethyl ester ( R ⁷ = -CH ₂ CH ₃ )

(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 100 mg, 0.3 mmol, 1.0 eq.), 5- (1-hydroxy- 1-methylethyl) -1H-pyrazole-3-carboxylic acid (73 mg, 429 μmol, 1.5 eq.), And HATU (160 mg, 430 μmol, 1.5 eq.) Were combined in DMF (5 mL) and The resulting mixture was stirred for 2 minutes. DIPEA (149 μl) was added and the mixture was stirred for 1 hour. Upon completion of the reaction, the mixture was dried in vacuo and then purified using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA) over 70 minutes to give the title compound as a TFA salt (50 mg). Obtained. MS m / z [M + H] ⁺ for C ₂₆ H ₃₁ N ₃ O ₅ , calculated 466.23; Found 466.4.

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (1-hydroxy- 1- methylethyl ) -1 H - pyrazole-3-carbonyl] Amino} pentanic acid ( R ⁷ = H)

2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 60 mg, 0.2 mmol, 1.0 eq.), 5- (1-hydroxy-1 -Methylethyl) -1H-pyrazole-3-carboxylic acid (43.8 mg, 257 μmol, 150 eq.), And HATU (98 mg, 260 μmol, 1.5 eq.) Were combined in DMF (5 mL), The resulting mixture was stirred for 2 minutes. DIPEA (89.6 μl) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum to afford crude ester. The crude ester was dissolved in ethanol (˜10 mL) and 10N NaOH was added to make the solution (˜200 μl) basic. The mixture was monitored over 1 hour until the final deprotection was complete. The mixture was acidified with equal volume (˜200 μL) of AcOH and dried under vacuum. The product was subjected to reverse phase chromatography to give the title compound (30 mg) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₄ H ₂₇ N ₃ O ₅ , calculated 438.20; Found 438.4.

Example 9

2- Hydroxypyrimidine -5- Carboxylic acid  ( (1R, 3R) -1-biphenyl-4- Yl methyl -3- Carbamoyl -3-hydroxypropyl) amide

(2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(2-hydroxypyrimidine-5 carbonyl) amino] pentanoic acid (14.5 mg, 35.6 μmol, 1.0 eq.) And HATU (13.5 mg, 35.6 μmol, 1.0 eq.) Were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. 0.5 M ammonia in dioxane was added followed by DIPEA (12.4 μl). The resulting mixture was stirred for 1 hour and then dried under vacuum. The product was purified using reverse phase chromatography (over 70 minutes, 10-70% MeCN / H ₂ O; 0.05% TFA) to afford the title compound (2 mg). MS m / z [M + H] ⁺ for C ₂₂ H ₂₂ N ₄ O ₄ , calculated 407.16; Found 407.4.

By following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, the compounds of Examples 10-15 with the following formulas were also prepared:

Example 10

These were prepared as parent compounds or TFA salts.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OCH ₂ CH ₃ H H C ₂₂ H ₂₄ N ₄ O ₄ 409.18 409.4 2 -OH H H C ₂₀ H ₂₀ N ₄ O ₄ 381.15 381.4

1. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) amino] pentanoic acid ethyl ester (TFA salt )

2. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) amino] pentanoic acid (TFA salt )

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 3 -OH -OH H C ₂₀ H ₂₀ N ₄ O ₅ 397.14 397.0 4 -OCH ₂ CH ₃ -OH H C ₂₂ H ₂₄ N ₄ O ₅ 425.17 425.2

3. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino ] -Pentanoic acid

4. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino ] -Pentanoic acid ethyl ester (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 5 -OCH ₂ CH ₃ H H C ₂₂ H ₂₄ N ₄ O ₄ 409.18 409.4 6 -OH H H C ₂₀ H ₂₀ N ₄ O ₄ 381.15 381.4 7 -OH -CH ₃ 4-Chlorophenyl C ₂₇ H ₂₅ ClN ₄ O ₄ 505.16 506.2 8 -OCH ₂ CH ₃ -OH H C ₂₂ H ₂₄ N ₄ O ₅ 425.17 425.2 9 -OH -OH H C ₂₀ H ₂₀ N ₄ O ₅ 397.14 397.2

5. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid ethyl ester (TFA salt )

6. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid (TFA salt)

7. (R) -5-Biphenyl-4-yl-4-{[1- (4-chlorophenyl) -5-methyl-1H- [1,2,4] triazole-3-carbonyl]- Amino} -2-hydroxypentanoic acid (TFA salt)

8. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-hydroxy-1H- [1,2,4] triazole-3-carbonyl) amino] -Pentanoic acid ethyl ester (TFA salt)

9. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-hydroxy-1H- [1,2,4] triazole-3-carbonyl) amino] -Pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 10 -OH 2-pyridine H C ₂₅ H ₂₃ N ₅ O ₄ 458.18 458.2

10. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-4H- [1,2,4] triazole-3-carbonyl) amino ] Pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 11 -OH -CH ₃ H C ₂₁ H ₂₂ N ₄ O ₄ 395.16 395.2 12 -OH -Cl H C ₂₀ H ₁₉ ClN ₄ O ₄ 415.11 415.4

11. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-methyl-2H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid ( TFA salt)

12. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-chloro-2H- [1,2,4] triazole-3-carbonyl) amino] -2-hydroxyphene Carbonic acid

Example 11

These were all prepared with TFA salts.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH H 3-carboxybenzyl C ₃₂ H ₂₈ N ₄ O ₆ 565.20 565.6 2 -OH H 4-carboxybenzyl C ₃₂ H ₂₈ N ₄ O ₆ 565.20 565.6 3 -OH H H C ₂₄ H ₂₂ N ₄ O ₄ 431.16 431.2 4 -OH F H C ₂₄ H ₂₁ FN ₄ O ₄ 449.15 449.0 5 -OCH ₂ CH ₃ Cl H C ₂₆ H ₂₅ ClN ₄ O ₄ 493.16 493.2

1. 3- [5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -benzotriazol-1-ylmethyl] -benzoic acid

2. 4- [5-( (1R, 3S) -1-Biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -benzotriazol-1-ylmethyl] -benzoic acid

3. (R) -4-[(1H-Benzotriazole-5-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid

4. (R) -5-Biphenyl-4-yl-4-[(7-fluoro-1H-benzotriazole-5-carbonyl) amino] -2-hydroxy-pentanoic acid

5. (R) -5-Biphenyl-4-yl-4-[(7-chloro-lH-benzotriazole-5-carbonyl) amino] -2-hydroxy-pentanoic acid ethyl ester

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 6 -OH -CH ₃ H C ₂₅ H ₂₄ N ₄ O ₄ 445.18 445.2

6. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(7-methyl-3H-benzotriazole-5-carbonyl) amino] pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 7 -OH Cl H C ₂₄ H ₂₁ ClN ₄ O ₄ 465.13 465.0

7. (R) -5-Biphenyl-4-yl-4-[(4-chloro-lH-benzotriazole-5-carbonyl) amino] -2-hydroxy-pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 8 -OH -CH ₃ H C ₂₆ H ₂₄ N ₂ O ₅ 445.17 445.4

8. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(2-methyl-benzooxazole-6-carbonyl) -amino] -pentanoic acid

XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 9 -OH H H C ₂₄ H ₂₂ N ₄ O ₄ 431.16 431.2

9. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H-imidazo [4,5-b] pyridine-6-carbonyl) -amino] -pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 10 -OCH ₂ CH ₃ H H C ₂₅ H ₂₅ N ₅ O ₄ 460.19 460.4 11 -OH H H C ₂₃ H ₂₁ N ₅ O ₄ 432.16 432.2

10. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl)- Amino] -pentanoic acid ethyl ester

11. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl)- Amino] -pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 12 -OCH ₂ CH ₃ H H C ₂₅ H ₂₅ N ₅ O ₄ 460.19 460.4 13 -OH H H C ₂₃ H ₂₁ N ₅ O ₄ 432.16 432.4 14 -OCH ₂ CH ₃ H H C ₂₅ H ₂₅ N ₅ O ₄ 460.19 460.4 15 -OH H H C ₂₃ H ₂₁ N ₅ O ₄ 432.16 432.4

12. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl ) -Amino] -pentanoic acid ethyl ester

13. (2S, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl ) -Amino] -pentanoic acid

14. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl ) -Amino] -pentanoic acid ethyl ester

15. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl ) -Amino] -pentanoic acid

Example 12

These were prepared as parent compounds or TFA salts.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH -COOH H C ₂₃ H ₂₁ NO ₇ 424.13 424.0

1. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) furan-2-carboxylic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 2 -OH -COOH H C ₂₃ H ₂₁ NO ₆ S 440.11 440.0

2. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) thiophene-2-carboxylic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 3 -OH -OCH ₃ H C ₂₂ H ₂₂ N ₂ O ₆ 411.15 411.2 4 -OH

H C ₂₇ H ₂₃ ClN ₂ O ₅ 491.13 491.2 5 -OH

H C ₂₉ H ₂₇ N ₃ O ₇ 530.19 530.4 6 -OH

H C ₂₇ H ₂₃ ClN ₂ O ₅ 491.13 491.4 7 -OH

H C ₂₇ H ₃₀ N ₂ O ₅ 463.22 463.4 8 -OH

H C ₂₇ H ₂₃ FN ₂ O ₅ 475.16 475.0 9 -OH

H C ₂₇ H ₂₃ FN ₂ O ₅ 475.16 475.0 10 -OH

H C ₂₅ H ₂₄ N ₄ O ₅ 461.17 461.2 11 -OH

H C ₂₇ H ₂₂ Cl ₂ N ₂ O ₅ 525.09 525.4 12 -OH

H C ₂₇ H ₂₂ Cl ₂ N ₂ O ₅ 525.09 525.4 13 -OH

H C ₂₈ H ₂₆ N ₂ O ₆ 487.18 487.2 14 -OH -COOH H C ₂₂ H ₂₀ N ₂ O ₇ 425.13 425.2

3. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3-methoxyisoxazole-5-carbonyl) amino] -pentanoic acid

4. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (4-chlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid ( TFA salt)

5. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[3- (2-methoxy-benzoylamino) -isoxazole-5-carbonyl] -amino}- Pentanic Acid (TFA Salt)

6. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (2-chlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid ( TFA salt)

7. (2R, 4R) -5-Biphenyl-4-yl-4-[(3-cyclohexyl-isoxazole-5-carbonyl) -amino] -2-hydroxy-pentanoic acid (TFA salt)

8. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (3-fluorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid

9. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (2-fluorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid

10. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[3- (1-methyl-1H-pyrazol-4-yl) -isoxazole-5-carbonyl ] -Amino} -pentanoic acid (TFA salt)

11. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (2,5-dichlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-phene Carbonic acid

12. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (3,4-dichlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-phene Carbonic acid

13. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[3- (2-methoxy-phenyl) -isoxazole-5-carbonyl] -amino} -phen Carbonic acid

14. 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -isoxazole-3-carboxylic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 15 -OH

H C ₂₈ H ₂₆ N ₂ O ₆ 487.18 487.4 16 -OH

H C ₂₇ H ₂₃ ClN ₂ O ₅ 491.13 491.4 17 -OH

H C ₂₇ H ₂₃ ClN ₂ O ₅ 491.13 491.2 18 -OH

H C ₂₈ H ₂₆ N ₂ O ₆ 487.18 487.2 19 -OH

H C ₂₆ H ₂₉ N ₃ O ₆ 480.21 480.2 20 -OH

H C ₂₈ H ₂₆ N ₂ O ₆ 487.18 487.2 21 -OH

H C ₂₇ H ₂₄ N ₂ O ₆ 473.16 473.0 22 -OH

H C ₂₈ H ₂₄ ClN ₃ O ₆ 534.14 535.0

15. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-phenyl) -isoxazole-3-carbonyl] -amino} -phen Carbonic Acid (TFA Salt)

16. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid ( TFA salt)

17. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (4-chlorophenyl) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid ( TFA salt)

18. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (3-methoxy-phenyl) -isoxazole-3-carbonyl] -amino} -phen Carbonic Acid (TFA Salt)

19. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-morpholin-4-ylmethyl-isoxazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)

20. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-methoxy-phenyl) -isoxazole-3-carbonyl] -amino} -phen Carbonic Acid (TFA Salt)

21. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-phenyl) -isoxazole-3-carbonyl] -amino} -phen Carbonic Acid (TFA Salt)

22. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 23 -OH Phenyl H C ₂₇ H ₂₄ N ₂ O ₅ 457.17 457.4

23. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(2-phenyl-oxazole-5-carbonyl) -amino] -pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 24 -OH -NHC (O) CH ₃ H C ₂₃ H ₂₃ N ₃ O ₅ S 454.14 454.2

24. (2R, 4R) -4-[(2-acetylamino-thiazole-5-carbonyl) -amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 25 -OH

H C ₂₉ H ₂₇ N ₃ O ₆ S 546.16 546.2

25. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[2- (2-methoxy-benzoylamino) -thiazole-4-carbonyl] -amino}- Pentanic Acid (TFA Salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 26 -OH 2-Chlorophenyl absence C ₂₆ H ₂₂ ClN ₃ O ₅ 492.12 492.4

26. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (2-chlorophenyl)-[1,2,4] oxadiazole-5-carbonyl] -amino}- 2-hydroxy-pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 27 -OH = O H C ₂₀ H ₁₉ N ₃ O ₆ 398.13 398.2

27. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-oxo-4,5-dihydro- [1,2,4] oxadiazole-3- Carbonyl) -amino] -pentanoic acid

Example 13

These were all prepared with the parent compound or TFA salt.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH -COOH H C ₂₃ H ₂₁ N ₃ O ₆ 436.14 436.2

1. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -pyrazine-2-carboxylic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 2 -OCH ₂ CH ₃ H H C ₂₄ H ₂₅ N ₃ O ₄ 420.18 420.4

2. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(pyrimidine-5-carbonyl) -amino] -pentanoic acid ethyl ester (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ Formula MS m / z : [M + H] < ⁺ > Calculated value Measures 3 -OH -COOH H C ₂₃ H ₂₁ N ₃ O ₆ 436.14 436.2 4 -OCH ₂ CH ₃ -OH H C ₂₄ H ₂₅ N ₃ O ₅ 436.18 436.4 5 -OH -OH H C ₂₂ H ₂₁ N ₃ O ₅ 408.15 408.2

3. 6-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -pyridazine-3-carboxylic acid (TFA salt)

4. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(6-hydroxypyridazine-3-carbonyl) -amino] -pentanoic acid ethyl ester

5. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(6-hydroxypyridazine-3-carbonyl) -amino] -pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 6 -OH H H C ₂₂ H ₂₃ N ₃ O ₅ 410.16 410.0

6. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(6-oxo-1,4,5,6-tetrahydro-pyridazine-3-carbonyl) -amino] -Pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 7 -OH -COOH H C ₂₄ H ₂₂ N ₂ O ₆ 435.15 435.2

7. 6-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) nicotinic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 8 -OH -COOH H C ₂₄ H ₂₂ N ₂ O ₆ 435.15 435.2

8. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -pyridine-2-carboxylic acid

Example 14

This was made with the parent compound.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH absence H C ₁₉ H ₁₉ N ₅ O ₄ 382.14 382.2

1. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H-tetrazol-5-carbonyl) amino] pentanoic acid

Example 15

These were prepared with TFA salts.

XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH H H C ₂₁ H ₂₁ N ₃ O ₄ 380.15 380.0 2 -OH -CH ₂ COOH H C ₂₃ H ₂₃ N ₃ O ₆ 438.16 438.4 3 -OH -CH ₂ OH H C ₂₂ H ₂₃ N ₃ O ₅ 410.16 410.4 4 -OH -CH ₂ OCH ₃ H C ₂₃ H ₂₅ N ₃ O ₅ 424.18 424.4 5 -OH -COOH -CH ₃ C ₂₃ H ₂₃ N ₃ O ₆ 438.16 438.4 6 -OH -COOH 3-SCF ₃ , 4-Cl-benzyl C ₃₀ H ₂₅ ClF ₃ N ₃ O ₆ S 648.11 648.0 7 -OH -COOH 3-Cl-benzyl C ₂₉ H ₂₆ ClN ₃ O ₆ 548.15 548.2 8 -OH -COOH 2,6-diF, 4-Cl-benzyl C ₂₉ H ₂₄ ClF ₂ N ₃ O ₆ 584.13 584.0 9 -OH -COOH 2-Cl-benzyl C ₂₉ H ₂₆ ClN ₃ O ₆ 548.15 548.2 10 -OH -COOH 2-Cl, 5-F-benzyl C ₂₉ H ₂₅ ClFN ₃ O ₆ 566.14 566.0 11 -OH -COOH 3-Cl, 5-F-benzyl C ₂₉ H ₂₅ ClFN ₃ O ₆ 566.14 566.0 12 -OH -COOH 3-OCF ₃ , 4-Cl-benzyl C ₃₀ H ₂₅ ClF ₃ N ₃ O ₇ 632.13 632.0 13 -OH -COOH 2-F, 4-Cl-benzyl C ₂₉ H ₂₅ ClFN ₃ O ₆ 566.14 566.2 14 -OH -COOH 3-Cl, 4-F-benzyl C ₂₉ H ₂₅ ClFN ₃ O ₆ 566.14 566.2 15 -OH -COOH 4-Cl-benzyl C ₂₉ H ₂₆ ClN ₃ O ₆ 548.15 548.2 16 -OH -COOH 2,6-diF, 3-Cl-benzyl C ₂₉ H ₂₄ ClF ₂ N ₃ O ₆ 584.13 584.0 17 -OH -COOH 3-methoxy-benzyl C ₃₀ H ₂₉ N ₃ O ₇ 544.20 544.2 18 -OCH ₂ -CH ₃ -C (O) O-CH ₂ CH ₃ H C ₂₆ H ₂₉ N ₃ O ₆ 480.21 480.2 19 -OH -CH ₃ H C ₂₂ H ₂₃ N ₃ O ₄ 394.17 394.2 20 -OH

H C ₂₆ H ₂₄ N ₄ O ₄ 457.18 457.4 21 -OH

H C ₂₆ H ₂₄ N ₄ O ₄ 457.18 457.2 22 -OH

H C ₂₅ H ₂₃ N ₅ O ₄ 458.18 458.2 23 -OH 1-methyl-1H-pyrazole H C ₂₅ H ₂₅ N ₅ O ₄ 460.19 460.2 24 -OH 2-Cl-phenyl H C ₂₇ H ₂₄ ClN ₃ O ₄ 490.15 490.0 25 -OH 3-Cl-phenyl H C ₂₇ H ₂₄ ClN ₃ O ₄ 490.15 490.4 26 -OH 2,4-diCl-phenyl H C ₂₇ H ₂₃ Cl ₂ N ₃ O ₄ 524.11 524.0 27 -OH 2,5-diCl-phenyl H C ₂₇ H ₂₃ Cl ₂ N ₃ O ₄ 524.11 524.0 28 -OH 2-hydroxy-phenyl H C ₂₇ H ₂₅ N ₃ O ₅ 472.18 472.6 29 -OCH ₂ -CH ₃ 2-hydroxy-phenyl H C ₂₉ H ₂₉ N ₃ O ₅ 500.21 500.4 30 -OH 2-hydroxy-phenyl -CH ₂ -CHOH-CH ₂ OH C ₃₀ H ₃₁ N ₃ O ₇ 546.22 546.4 31 -OH 3-NHC (O) -CH ₃ -phenyl H C ₂₉ H ₂₈ N ₄ O ₅ 513.21 513.2 32 -OH

H C ₂₉ H ₂₈ N ₄ O ₆ 529.20 530.4 33 -OH Phenyl H C ₂₇ H ₂₅ N ₃ O ₄ 456.18 456.2 34 -OH Phenyl -CH ₃ C ₂₈ H ₂₇ N ₃ O ₄ 470.20 470.2 35 -OH Phenyl -CH ₂ -COOH C ₂₉ H ₂₇ N ₃ O ₆ 514.19 514.6 36 -OH Phenyl -(CH ₂ ) ₂ -COOH C ₃₀ H ₂₉ N ₃ O ₆ 528.21 528.2 37 -OH Furan H C ₂₅ H ₂₃ N ₃ O ₅ 446.16 446.2 38 -OH Naphthyl H C ₃₁ H ₂₇ N ₃ O ₄ 506.20 506.2 39 -OH 4-biphenyl H C ₃₃ H ₂₉ N ₃ O ₄ 532.22 532.2 40 -OH 4-Cl-phenyl H C ₂₇ H ₂₄ ClN ₃ O ₄ 490.15 490.2 41

-C (CH ₃ ) ₂ OH H C ₂₉ H ₃₁ N ₃ O ₈ 550.21 550.4

1. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H-pyrazole-3-carbonyl) amino] pentanoic acid

2. (2R, 4R) -5-biphenyl-4-yl-4-[(5-carboxymethyl-1H-pyrazole-3-carbonyl) amino] -2-hydroxy-pentanoic acid

3. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-hydroxymethyl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid

4. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-methoxymethyl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid

5. 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2-methyl-2H-pyrazole-3-carboxylic acid

6. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2- (4-chloro-3-trifluoromethylsulfanyl-benzyl ) -2H-pyrazole-3-carboxylic acid

7. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2- (3-chlorobenzyl) -2H-pyrazole-3-carbox Acid

8. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chloro-2,6-difluorobenzyl) -2H-pyrazole-3-carboxylic acid

9. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (2-chlorobenzyl) -2H-pyrazole-3- Carboxylic acid

10. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (2-chloro-5-fluorobenzyl) -2H- Pyrazole-3-carboxylic acid

11.5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-chloro-5-fluorobenzyl) -2H- Pyrazole-3-carboxylic acid

12. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chloro-3-trifluoromethoxybenzyl)- 2H-pyrazole-3-carboxylic acid

13. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chloro-2-fluorobenzyl) -2H- Pyrazole-3-carboxylic acid

14. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-chloro-4-fluorobenzyl) -2H- Pyrazole-3-carboxylic acid

15. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chlorobenzyl) -2H-pyrazole-3- Carboxylic acid

16. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-chloro-2,6-difluorobenzyl) -2H-pyrazole-3-carboxylic acid

17. 5-( (R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-methoxy-benzyl) -2H-pyrazole- 3-carboxylic acid

18. 5-( (R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxy-propylcarbamoyl) -2H-pyrazole-3-carboxylic acid ethyl ester

19. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-methyl-1H-pyrazole-3-carbonyl) amino] pentanoic acid

20. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-4-yl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid

21. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-3-yl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid

22. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyrazin-2-yl-1H-pyrazole-3-carbonyl) amino] -pentanoic acid

23. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1'-methyl-2H, 1'H- [3,4 '] bipyrazolyl-5-carbonyl) Amino] -pentanoic acid

24. (R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -1 H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid

25. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (3-chlorophenyl) -1 H-pyrazole-3-carbonyl] -amino} -2-hydroxy-phene Carbonic acid

26. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2,4-dichlorophenyl) -1 H-pyrazole-3-carbonyl] -amino} -2-hydroxy -Pentanoic acid

27. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2,5-dichlorophenyl) -1 H-pyrazole-3-carbonyl] -amino} -2-hydroxy -Pentanoic acid

28. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-phenyl) -1 H-pyrazole-3-carbonyl] -amino} -Pentanoic acid

29. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-phenyl) -1 H-pyrazole-3-carbonyl] -amino} -Pentanoic acid ethyl ester

30. (2R, 4R) -5-Biphenyl-4-yl-4-{[1- (2,3-dihydroxy-propyl) -5- (2-hydroxy-phenyl) -1 H-pyrazole 3-carbonyl] -amino} -2-hydroxy-pentanoic acid

31. (R) -4-{[5- (3-acetylamino-phenyl) -1H-pyrazol-3-carbonyl] amino} -5-biphenyl-4-yl-2-hydroxypentanoic acid

32. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-benzoylamino) -1 H-pyrazole-3-carbonyl] -amino } -Pentanoic acid

33. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-phenyl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid

34. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1-methyl-5-phenyl-1 H-pyrazole-3-carbonyl) amino] -pentanoic acid

35. (2R, 4R) -5-Biphenyl-4-yl-4-[(1-carboxymethyl-5-phenyl-1 H-pyrazole-3-carbonyl) -amino] -2-hydroxy-phene Carbonic acid

36. (2R, 4R) -5-Biphenyl-4-yl-4-{[1- (2-carboxy-ethyl) -5-phenyl-1 H-pyrazole-3-carbonyl] -amino} -2 Hydroxy-pentanoic acid

37. (R) -5-Biphenyl-4-yl-4-[(5-furan-2-yl-1H-pyrazole-3-carbonyl) amino] -2-hydroxy-pentanoic acid

38. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-naphthalen-2-yl-1H-pyrazole-3-carbonyl) amino] -pentanoic acid

39. (R) -5-Biphenyl-4-yl-4-[(5-biphenyl-4-yl-1H-pyrazole-3-carbonyl) amino] -2-hydroxy-pentanoic acid

40. (R) -5-Biphenyl-4-yl-4-{[5- (4-chlorophenyl) -1H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid

41. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (1-hydroxy-1-methylethyl) -1 H-pyrazole-3-carbonyl] Amino} pentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 42 -OH

H C ₂₆ H ₂₈ N ₄ O ₆ 493.20 493.2 43 -OCH ₂ -CH ₃

H C ₂₉ H ₃₃ N ₅ O ₆ 548.24 548.2 44 -OH

H C ₂₇ H ₂₉ N ₅ O ₆ 520.21 520.2 45 -OCH ₂ -CH ₃

H C ₂₉ H ₃₃ N ₅ O ₆ 548.24 548.2 46 -OH

H C ₂₇ H ₂₉ N ₅ O ₆ 520.21 520.2 47 -OCH ₂ -CH ₃

H C ₂₉ H ₃₄ N ₄ O ₆ 535.25 535.2 48 -OH

H C ₂₇ H ₃₀ N ₄ O ₆ 507.22 507.2 49 -OCH ₂ -CH ₃

H C ₂₉ H ₃₄ N ₄ O ₆ 535.25 535.2 50 -OH

H C ₂₇ H ₃₀ N ₄ O ₆ 507.22 507.2 51 -OCH ₂ -CH ₃

H C ₂₈ H ₃₂ N ₄ O ₆ 521.23 521.4 52 -OCH ₂ -CH ₃ -C (O) NH-cyclopropyl H C ₂₇ H ₃₀ N ₄ O ₅ 491.22 491.2 53 -OH

H C ₂₆ H ₂₈ N ₄ O ₆ 493.20 493.2 54 -OCH ₂ -CH ₃ -C (O) NH-cyclopropyl H C ₂₇ H ₃₀ N ₄ O ₅ 491.22 491.2 55 -OH -C (O) NH-cyclopropyl H C ₂₅ H ₂₆ N ₄ O ₅ 463.19 463.2 56 -OH -C (O) NH-CH ₂ COOH H C ₂₄ H ₂₄ N ₄ O ₇ 481.16 481.2 57 -OH -C (O) NH-cyclopropyl H C ₂₅ H ₂₆ N ₄ O ₅ 463.19 463.2 58 -OCH ₂ -CH ₃ -C (O) NH ₂ H C ₂₄ H ₂₆ N ₄ O ₅ 451.19 451.2 59 -OH -C (O) NH ₂ H C ₂₂ H ₂₂ N ₄ O ₅ 423.16 424.0 60 -OH -C (O) -NHCH ₃ H C ₂₃ H ₂₄ N ₄ O ₅ 437.17 437.4 61 -OH -C (O) NH- (CH ₂ ) ₂ CH ₃ H C ₂₅ H ₂₈ N ₄ O ₅ 465.21 465.2 62 -OCH ₂ -CH ₃ -C (O) -N (CH ₃ ) ₂ H C ₂₆ H ₃₀ N ₄ O ₅ 479.22 479.2 63 -OH -C (O) -N (CH ₃ ) ₂ H C ₂₄ H ₂₆ N ₄ O ₅ 451.19 451.2 64 -OCH ₂ -CH ₃ -C (O) -N (CH ₃ ) -CH ₂ -CH (CH ₃ ) ₂ H C ₂₉ H ₃₆ N ₄ O ₅ 521.27 521.2 65 -OH -C (O) -N (CH ₃ ) -CH ₂ -CH (CH ₃ ) ₂ H C ₂₇ H ₃₂ N ₄ O ₅ 493.24 493.2 66 -OCH ₂ -CH ₃ -C (O) -N (CH ₃ ) -CH ₂ -CH (CH ₃ ) ₂ H C ₂₉ H ₃₆ N ₄ O ₅ 521.27 521.2 67 -OH -C (O) -N (CH ₃ ) -CH ₂ -CH (CH ₃ ) ₂ H C ₂₇ H ₃₂ N ₄ O ₅ 493.24 493.4 68 -OCH ₂ -CH ₃ -C (O) NH- (CH ₂ ) ₂ -imidazole H C ₂₉ H ₃₂ N ₆ O ₅ 545.24 545.2 69 -OH -C (O) NH- (CH ₂ ) ₂ -imidazole H C ₂₇ H ₂₈ N ₆ O ₅ 517.21 517.2 70 -OH -C (O) -NH- (CH ₂ ) ₂ -OH H C ₂₄ H ₂₆ N ₄ O ₆ 467.19 467.2 71 -OH -C (O) NH- (CH ₂ ) ₂ -N (CH ₃ ) ₂ H C ₂₆ H ₃₁ N ₅ O ₅ 494.23 494.2 72 -OH Cyclopropyl H C ₂₄ H ₂₅ N ₃ O ₄ 420.18 420.2 73 -OH -CH (CH _{3) 2} H C ₂₄ H ₂₇ N ₃ O ₄ 422.20 422.2 74 -OH -(CH ₂ ) ₂ -CH ₃ H C ₂₄ H ₂₇ N ₃ O ₄ 422.20 422.2 75 -OH -(CH ₂ ) ₃ -CH ₃ H C ₂₅ H ₂₉ N ₃ O ₄ 436.22 436.2 76 -OH Phenyl H C ₂₇ H ₂₅ N ₃ O ₄ 456.18 456.2 77 -OH Phenyl -(CH ₂ ) ₂ -COOH C ₃₀ H ₂₉ N ₃ O ₆ 528.21 528.4 78 -OH 2-hydroxy-phenyl -CH ₂ -CHOH-CH ₂ OH C ₃₀ H ₃₁ N ₃ O ₇ 546.22 546.2 79 -OH 2-methoxy-phenyl H C ₂₈ H ₂₇ N ₃ O ₅ 486.20 486.6 80 -OH 2,5-dimethoxy-phenyl H C ₂₉ H ₂₉ N ₃ O ₆ 516.21 516.2 81 -OH 2-CF ₃ -phenyl H C ₂₈ H ₂₄ F ₃ N ₃ O ₄ 524.17 524.2 82 -OH 4-F-phenyl H C ₂₇ H ₂₄ FN ₃ O ₄ 474.18 474.2 83 -OH 4-Cl-phenyl H C ₂₇ H ₂₄ ClN ₃ O ₄ 490.15 490.4 84 -OH 2-Cl-phenyl H C ₂₇ H ₂₄ ClN ₃ O ₄ 490.15 490.4 85 -OCH ₂ -CH ₃ 2-Cl-phenyl H C ₂₉ H ₂₈ ClN ₃ O ₄ 518.18 518.4 86 -OH 2-methoxy, 5-fluorophenyl H C ₂₈ H ₂₆ FN ₃ O ₅ 504.19 504.2 87 -OCH- (CH ₃ ) ₂ 2-methoxy, 5-fluorophenyl H C ₃₁ H ₃₂ FN ₃ O ₅ 546.23 546.2 88 -OCH ₂ -CH ₃ 2-methoxy, 5-fluoro-phenyl H C ₃₀ H ₃₀ FN ₃ O ₅ 532.22 532.4 89 -OH 2-methyl-thiophene H C ₂₆ H ₂₅ N ₃ O ₄ S 476.16 476.0 90 -OH 2-chloro-thiophene H C ₂₅ H ₂₂ ClN ₃ O ₄ S 496.10 497.0 91 -OH -NHC (O) -CH ₂ CH ₃ H C ₂₄ H ₂₆ N ₄ O ₅ 451.19 451.2 92 -OH -NHC (O)-(CH ₂ ) ₃ CH ₃ H C ₂₆ H ₃₀ N ₄ O ₅ 479.22 479.2 93 -OH -NHC (O) -O-CH ₂ CH ₃ H C ₂₄ H ₂₆ N ₄ O ₆ 467.19 467.2 94 -OH -NHC (O) -CH ₂ -OCH ₃ H C ₂₄ H ₂₆ N ₄ O ₆ 467.19 467.2 95 -OH -NHC (O) -2-methoxy-phenyl H C ₂₉ H ₂₈ N ₄ O ₆ 529.20 529.2 96 -OH

H C ₂₈ H ₂₅ ClN ₄ O ₅ 533.15 533.2 97 -OCH ₂ -CH ₃

H C ₃₀ H ₂₉ ClN ₄ O ₅ 561.18 561.2 98 -OCH ₂ -CH- (CH ₃ ) ₂

H C ₃₂ H ₃₃ ClN ₄ O ₅ 589.21 589.2 99 -O-CH- (CH ₃ ) ₂

H C ₃₁ H ₃₁ ClN ₄ O ₅ 575.20 575.2 100 -OH -NHC (O) -2-pyridine H C ₂₇ H ₂₅ N ₅ O ₅ 500.19 500.2 101 -OH -NH ₂ H C ₂₁ H ₂₂ N ₄ O ₄ 395.16 395.0 102 -OH

H C ₂₆ H ₂₄ N ₄ O ₄ 457.18 457.6 103 -OCH ₂ -CH ₃

H C ₂₈ H ₂₈ N ₄ O ₄ 485.21 485.6 104 -OCH ₂ -CH- (CH ₃ ) ₂

H C ₃₀ H ₃₂ N ₄ O ₄ 513.24 513.6 105

H C ₃₁ H ₂₈ N ₄ O ₇ 569.20 569.4 106 -OH Pyrazine H C ₂₅ H ₂₃ N ₅ O ₄ 458.18 458.2 107 -O-CH- (CH ₃ ) OC (O) O-cyclo-hexyl -C (O) CH ₃ H C ₃₂ H ₃₇ N ₃ O ₈ 592.26 592.6 108 -NH ₂ -C (O) CH ₃ H C ₂₃ H ₂₄ N ₄ O ₄ 421.18 421.2 109 -OH -CH (OH) -CH ₃ H C ₂₃ H ₂₅ N ₃ O ₅ 424.18 424.2 110 -OH -CH (OH) -CH ₃ H C ₂₃ H ₂₅ N ₃ O ₅ 424.18 424.4 111 -OH -C (CH ₃ )
= N (OH) H C ₂₃ H ₂₄ N ₄ O ₅ 437.17 437.4 112 -OH -(CH ₂ ) ₃ -CH ₃ H C ₂₅ H ₂₉ N ₃ O ₄ 436.22 436.4

42. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (3-hydroxypyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl ] -Amino} -pentanoic acid

43. (2S, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl]- Amino} -2-hydroxy-pentanoic acid ethyl ester

44. (2S, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl]- Amino} -2-hydroxy-pentanoic acid

45. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl]- Amino} -2-hydroxy-pentanoic acid ethyl ester

46. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl]- Amino} -2-hydroxy-pentanoic acid

47. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3- Carbonyl] -amino} -pentanoic acid ethyl ester

48. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3- Carbonyl] -amino} -pentanoic acid

49. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3- Carbonyl] amino} -pentanoic acid ethyl ester

50. (2S, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3- Carbonyl] -amino} -pentanoic acid

51. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (morpholin-4-carbonyl) -2H-pyrazole-3-carbonyl] -amino}- Pentanoic acid ethyl ester

52. (2S, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid ethyl ester

53. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (morpholin-4-carbonyl) -2H-pyrazole-3-carbonyl] amino} pentanoic acid

54. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid ester

55. (2S, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid

56. (R) -5-Biphenyl-4-yl-4-{[5- (carboxymethyl-carbamoyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-phene Carbonic acid

57. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid

58. (R) -5-Biphenyl-4-yl-4-[(5-carbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid ethyl ester

59. (R) -5-Biphenyl-4-yl-4-[(5-carbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

60. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-methylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] pentanoic acid

61. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-propylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] pentanoic acid

62. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-dimethylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid ethyl ester

63. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-dimethylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

64. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (isobutyl-methyl-carbamoyl) -2H-pyrazole-3-carbonyl]- Amino} -pentanoic acid ethyl ester

65. (2S, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (isobutylmethyl-carbamoyl) -2H-pyrazole-3-carbonyl] amino} -Pentanoic acid

66. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (isobutylmethyl-carbamoyl) -2H-pyrazole-3-carbonyl] amino} -Pentanoic acid ethyl ester

67. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (isobutylmethyl-carbamoyl) -2H-pyrazole-3-carbonyl] amino} -Pentanoic acid

68. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5- [2- (1H-imidazol-4-yl) -ethylcarbamoyl] -2H- Pyrazole-3-carbonyl} amino) pentanoic acid ethyl ester

69. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5- [2- (3H-imidazol-4-yl) -ethylcarbamoyl] -2H- Pyrazole-3-carbonyl} amino) pentanoic acid

70. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-ethylcarbamoyl) -2H-pyrazole-3-carbonyl] -amino } -Pentanoic acid

71. (R) -5-Biphenyl-4-yl-4-{[5- (2-dimethylamino-ethylcarbamoyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydrate Roxy-pentanoic acid

72. (R) -5-Biphenyl-4-yl-4-[(5-cyclopropyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

73. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-isopropyl-2H-pyrazole-3-carbonyl) amino] -pentanoic acid

74. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-propyl-2H-pyrazole-3-carbonyl) amino] -pentanoic acid

75. (R) -5-Biphenyl-4-yl-4-[(5-butyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

76. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-phenyl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid

77. (2R, 4R) -5-Biphenyl-4-yl-4-{[2- (2-carboxy-ethyl) -5-phenyl-2H-pyrazole-3-carbonyl] -amino} -2 Hydroxy-pentanoic acid

78. (2R, 4R) -5-Biphenyl-4-yl-4-{[2- (2,3-dihydroxy-propyl) -5- (2-hydroxy-phenyl) -2H-pyrazole 3-carbonyl] -amino} -2-hydroxy-pentanoic acid

79. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -Pentanoic acid

80. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2,5-dimethoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -2- Hydroxy-pentanoic acid

81. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-trifluoromethyl-phenyl) -2H-pyrazole-3-carbonyl] -amino} -Pentanoic acid

82. (R) -5-Biphenyl-4-yl-4-{[5- (4-fluorophenyl) -2H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid

83. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (4-chlorophenyl) -2H-pyrazole-3-carbonyl]-

84. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -2H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid

85. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-phene Carbonic acid ethyl ester

86. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-fluoro-2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} 2-hydroxy-pentanoic acid

87. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-fluoro-2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} 2-hydroxy-pentanoic acid isopropyl ester (HCL salt)

88. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-fluoro-2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} 2-hydroxy-pentanoic acid ethyl ester

89. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (5-methylthiophen-2-yl) -2H-pyrazole-3-carbonyl] -Amino} -pentanoic acid

90. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-chlorothiophen-2-yl) -2H-pyrazole-3-carbonyl] -amino} -2 Hydroxy-pentanoic acid

91. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-propionylamino-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid

92. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pentanoylamino-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid

93. (R) -5-Biphenyl-4-yl-4-[(5-ethoxycarbonylamino-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

94. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-acetylamino) -2H-pyrazole-3-carbonyl] -amino}- Pentanic acid

95. (R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-benzoylamino) -2H-pyrazole-3-carbonyl] -amino}- Pentanic acid

96. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy- Pentanic acid

97. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy- Pentanoic acid ethyl ester

98. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy- Pentanic acid isobutyl ester

99. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy- Pentanic acid isopropyl ester

100. (R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(pyridine-2-carbonyl) -amino] -2H-pyrazole-3-carbonyl}- Amino) -pentanoic acid

101. (R) -4-[(5-amino-2H-pyrazole-3-carbonyl) -amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid

102. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid

103. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid Ethyl ester

104. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid Isobutyl ester

105. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

106. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazole-3-carbonyl) -amino] pentanoic acid

107. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid 1-cyclohexyloxane Cycarbonyloxyethyl ester

108. 5-Acetyl-2H-pyrazole-3-carboxylic acid ((1R, 3R) -1-biphenyl-4-ylmethyl-3-carbamoyl-3-hydroxypropyl) amide

109. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5-( (S) -1-hydroxyethyl) -2H-pyrazole-3-carbonyl] Amino} pentanoic acid

110. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5-( (R) -1-hydroxyethyl) -2H-pyrazole-3-carbonyl] Amino} pentanoic acid

111. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5- {1-[(E) -hydroxyimino] -ethyl} -2H-pyrazole-3 -Carbonyl) -amino] -pentanoic acid

112. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-butyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 113 -OH H H C ₂₁ H ₂₁ N ₃ O ₄ 380.15 380.2

113. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H-pyrazole-4-carbonyl) amino] pentanoic acid

Example 16

Following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, compounds having the following formula were prepared as TFA salts.

Ex. -XR ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One

C ₂₉ H ₂₇ N ₃ O ₅ 498.20 498.8 2

C ₂₉ H ₂₇ N ₃ O ₅ 498.20 498.6 3

C ₃₀ H ₂₉ N ₃ O ₅ 512.21 512.6 4

C ₃₀ H ₂₉ N ₃ O ₆ 528.21 528.4 5

C ₃₀ H ₂₉ N ₃ O ₆ 528.21 528.4 6

C ₂₈ H ₂₅ N ₃ O ₅ 484.18 484.6

1. (2R, 4R) -5-Biphenyl-4-yl-4-[(4,5-dihydro-6-oxa-3,3a-diaza-benzo [e] azulene-2-carbonyl ) -Amino] -2-hydroxy-pentanoic acid

2. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(8-oxa-11,14-diaza-tricyclo [9.2.1.02,7] tetradeca-1 (14), 2,4,6,12-pentaene-12-carbonyl) -amino] -pentanoic acid

3. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(10-oxa-5,6-diaza-tricyclo [9.4.0.02,6] pentadeca-1 (15), 2,4,11,13-pentaene-4-carbonyl) -amino] -pentanoic acid

4. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[((S) -8-hydroxy-10-oxa-5,6-diaza-tricyclo [9.4 .0.02,6] pentadeca-1 (15), 2,4,11,13-pentaene-4-carbonyl) -amino] -pentanoic acid

5. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[((R) -8-hydroxy-10-oxa-5,6-diaza-tricyclo [9.4 .0.02,6] pentadeca-1 (15), 2,4,11,13-pentaene-4-carbonyl) -amino] -pentanoic acid

6. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-oxa-3,3a-diaza-cyclopenta [a] naphthalene-2-carbonyl)- Amino] -pentanoic acid

Production Example 9

(S) -2- (4- Bromobenzyl ) -5- Oxopyrrolidine -One- Carboxylic acid t - butyl ester

To a solution of ( R) -2-amino-3- (4-bromophenyl) propionic acid (50 g, 0.2 mol) in MeCN (700 mL) was added a solution of NaOH (16.4 g, 0.4 mol) in water (700 mL). Add at -5 ° C. After stirring for 10 minutes, a solution of (Boc) ₂ O (44.7 g, 0.2 mol) in MeCN (100 mL) was added. The resulting mixture was allowed to warm up to room temperature and stirred overnight. After evaporation of MeCN, the residue was diluted with DCM (800 mL) and acidified to pH = 2 with 1 M HCl at −5 ° C. The aqueous solution was extracted with DCM (3 × 200 mL). The combined organic layers were washed with saturated aqueous NaCl solution (500 mL), dried over Na ₂ SO ₄ , and concentrated to give compound 1 (66.5 g) as a white solid. LC-MS: 366 (M + Na), 709 (2M + Na).

To a solution of compound 1 (66.5 g, 193 μmol), meldmic acid (33.4 g, 232 mmol) and DMAP (37.7 g, 309 mmol) in dry DCM (600 mL), DCC (47.9 in dry DCM (200 mL)) g, 232 mmol) was added dropwise over 1 hour at −5 ° C. under nitrogen. The resulting mixture was stirred at -5 ° C for 8 hours and then refrigerated overnight. Dicyclohexylurea crystals were observed. The mixture was filtered, washed with 5% KHSO ₄ (5 × 200 mL), saturated aqueous NaCl solution (200 mL) and dried over anhydrous MgSO ₄ overnight under refrigeration. The resulting solution was then evaporated to afford crude compound 2 (91 g) as a pale yellow solid. LC-MS: 492 (M + Na), 961 (2M + Na).

To a solution of crude compound 2 (91 g, 193 mmol) in anhydrous DCM (1 L) was added AcOH (127.5 g, 2.1 mol) at −5 ° C. under nitrogen. The resulting mixture was stirred at −5 ° C. for 30 minutes and then NaBH ₄ (18.3 g, 483 mmol) was added in small portions over 1 hour. After stirring at −5 ° C. for 1 h, saturated aqueous NaCl solution (500 mL) was added. The organic layer was washed with saturated aqueous NaCl solution (2 × 300 mL) and water (2 × 300 mL), dried over MgSO ₄ , filtered and concentrated to give crude product, which was further purified by washing with Et ₂ O, pale. Compound 3 (68 g) was obtained as a yellow solid. LC-MS: 478 (M + Na), 933 (2M + Na).

A solution of compound 3 (68 g, 149 mmol) in anhydrous toluene (500 mL) was refluxed under nitrogen for 3 hours. After evaporation of the solvent, the residue was purified by chromatography (hexane: EtOAc = 10: 1) to afford the title compound (38 g) as a pale yellow oil. LC-MS: 376 (M + Na), 729 (2M + Na).

Production Example 10

(2R, 4R) -4-amino-5- (4- Bromophenyl )-2- Hydroxypentanoic acid  Ethyl ester

To a solution of (S) -2- (4-bromobenzyl) -5-oxopyrrolidine-1-carboxylic acid t -butyl ester (38 g, 107 mmol) in anhydrous DCM (250 mL), TFA ( 20 mL, 0.27 mol) was added at -5 ° C under nitrogen. The mixture was allowed to warm up to room temperature and stirred overnight. After evaporation of the solvent, the residue is diluted with EtOAc (300 mL), washed with saturated aqueous NaHCO ₃ ( ₃ × 200 mL), water (200 mL), saturated aqueous NaCl solution (250 mL), dried over Na ₂ SO _4, and Concentration gave crude compound 1 (24 g) as a pale yellow solid. LC-MS: 254 (M + H).

To a solution of NaH (8.6 g, 250 mmol) in anhydrous THF (200 mL) was added a solution of compound 1 (24 g, 94 mmol) in anhydrous THF (200 mL) over 30 minutes at 0 ° C. under nitrogen. The resulting mixture was allowed to warm up to room temperature and stirred for 2 hours. After cooling to 0 ° C. pivaloyl chloride (18 g, 150 mmol) was added dropwise over 30 minutes. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH ₄ Cl solution (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with saturated aqueous NaCl solution (300 mL), dried over MgSO ₄ , filtered and concentrated to afford crude product, which was further purified by chromatography (hexane: EtOAc = 25: 1), Compound 2 (18 g) was obtained as a pale yellow solid. LC-MS: 360 (M + Na).

To a solution of compound 2 (18 g, 53 mmol) in anhydrous THF (250 mL), HMDSNa (47.7 mL, 96 mmol) was added dropwise over 30 minutes at −78 ^° C. under nitrogen. After stirring at −78 ^° C. for 90 minutes, a solution of (+)-(8,8-dichlorocamphorylsulfonyl) oxaziridine (31.6 g, 106 mmol) was added dropwise over 30 minutes. After stirring at −78 ^° C. for 2 hours, the reaction was quenched with saturated aqueous NH ₄ Cl solution (400 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated aqueous NaCl solution (300 mL), dried over MgSO ₄ , filtered and concentrated to give crude product, which was further purified by chromatography (hexane: EtOAc = 15: 1) to give a pale yellow color. Compound 3 (8.9 g) was obtained as a solid. LC-MS: 376 (M + Na).

A solution of compound 3 (8.9 g, 25 mmol) in concentrated HCl (81 mL, 81 mmol) was heated at 100 ° C. for 6 h. The resulting mixture was then concentrated to give crude product, which was further purified by washing with Et ₂ O to afford compound 4 (7 g) as a pale yellow solid HCl salt. LC-MS: 323 (M + H).

A solution of compound 4 (7 g, 22 mmol) in ethanol (10 mL) was combined with 8M HCl in ethanol (120 mL, 960 mmol) at room temperature. The resulting mixture was heated at 50 ° C. for 16 hours and then concentrated. The crude compound was further purified by washing with Et ₂ O to afford the title compound (6 g) as a pale yellow solid HCl salt. LC-MS: 352 (M + H).

Production Example 11

1-hydroxy-1H-1,2,3- Triazole -4- Carboxylic acid

1-hydroxy-1H- [1,2,3] triazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol) and ethanol (25 mL) were added to lithium hydroxide monohydrate (1.6 g, 38.2). mmol) and water (10 mL) in combination with a pre-dissolved solution and stirred at room temperature for 4 hours. The resulting mixture was partially concentrated and acidified with HCl to cause precipitation. The solid was filtered and dried under vacuo to yield the title compound (1.3 g).

Production Example 12

(2R, 4R) -5- (4- Bromo - Phenyl ) -2-hydroxy-4 - [(1-hydroxy-1H-1,2,3- Triazole -4-carbonyl) -amino] - Pentanoic acid  Ethyl ester

1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (163 mg, 1.3 mmol),), HCTU (523 mg, 1.3 mmol), and DMF were combined and 5 minutes at room temperature Was stirred. DIPEA (661 μl, 3.8 mmol) and (2R, 4R) -4-amino-5- (4-bromophenyl) -2-hydroxypentanoic acid ethyl ester (4 mg, 1.3 mmol) were added and the resulting mixture Was stirred for 10 minutes. The reaction mixture was evaporated under reduced pressure and purified (C18 column; 20-70% MeCN in water, including 0.05% TFA) to give the title compound (330 mg).

Example 17

A. (2R, 4R) -5- (3' -Chlorobiphenyl- 4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] pentanoic acid

1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (17.6 mg, 136 μmol) and HCTU (56.4 mg, 136 μmol) were combined in DMF and stirred at room temperature for 5 minutes. . DIPEA (71.2 μl, 409 μmol) and (2R, 4R) -4-amino-5- (4-bromophenyl) -2-hydroxypentanoic acid ethyl ester (43 mg, 140 μmol) were added and the resulting mixture Was stirred for 10 minutes. The reaction mixture obtained was evaporated under reduced pressure and purified (C18 reversed phase column). The purified material was combined with 3-chlorophenylboronic acid, pinacol esters (48.1 mg, 202 μmol), K ₂ CO ₃ (41.8 mg, 302 μmol), ethanol (1 ml) and water (0.3 ml). Oxygen was removed (high vacuum) and SilicaCat® Pd (0) (0.09 mmol / g loading; 112 mg, 10.1 μmol) was added rapidly under nitrogen. The mixture was microwaved at 100 ° C. for 20 minutes and concentrated. The material obtained was redissolved in AcOH and purified by preparative HPLC to give the title compound (12 mg; purity 95%). MS m / z [M + H] ⁺ for C ₂₀ H ₁₉ ClN ₄ O ₅ , calculated 431.10. Found 431.4.

B. (2R, 4R) -5- (3' -Chlorobiphenyl- 4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] pentanoic acid ethyl ester

(2R, 4R) -5- (4-Bromo-phenyl) -2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl) -amino] Pentanoic acid ethyl ester (120 mg, 281 μmol) and 3-chlorophenylboronic acid, pinacol ester (120 mg, 506 μmol) were added to K ₂ CO ₃ (116 mg, 842 μmol), ethanol (3 mL), and Combined with water (0.8 mL). SilicaCat ^® DPP-Pd (280 μmol / g loading; 1 mg, 28 μmol) was then added and the resulting mixture was heated at 90 ° C. and the reaction was monitored by LC / MS. The reaction was stopped after 2 hours and the mixture was filtered, concentrated and purified (C18 reverse phase column; 30-70% MeCN in water, containing 0.05% TFA). Ethanol (5.0 mL, 86 mmol) and 4 M HCl (1.5 mL, 6.0 mmol) in dioxane were added and the resulting mixture was stirred at room temperature for 40 minutes, then concentrated and purified (C18 reverse phase column; 0.05% TFA). 30-90% MeCN in water), title compound (20 mg; purity 95%) was obtained. MS m / z [M + H] ⁺ for C ₂₂ H ₂₃ ClN ₄ O ₅ , calculated 459.14; Found 459.4.

Example 18

Following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, compounds having the following formulas were prepared as parent compounds or TFA salts.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OCH ₂ CH ₃ H H C ₂₂ H ₂₃ ClN ₄ O ₄ 443.14 443.4

1. (2R, 4R) -5 (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl)- Amino] -pentanoic acid ethyl ester (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 2 -OH H H C ₂₀ H ₁₉ ClN ₄ O ₄ 415.11 415.4

2. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(1H- [1,2,3] triazole-4-carbonyl)- Amino] -pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 3 -OH H -OH C ₂₄ H ₂₁ ClN ₄ O ₅ 481.12 481.2 4 -OCH ₂ CH ₃ H -OH C ₂₆ H ₂₅ ClN ₄ O ₅ 509.15 509.2

3. (2R, 4R) -5 (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino ] -Pentanoic acid

4. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino ] -Pentanoic acid ethyl ester

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 5 -OCH ₂ CH (CH ₃ ) ₂ H -OH C ₂₈ H ₂₉ ClN ₄ O ₅ 537.18 537.2 6 -OCH (CH ₃ ) ₂ H -OH C ₂₇ H ₂₇ ClN ₄ O ₅ 523.17 523.2

5. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino ] -Pentanoic acid isobutyl ester

6. (2R, 4R) -5 (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino ] -Pentanoic acid isopropyl ester

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 7 -OH -C (O) CH ₃ H C ₂₃ H ₂₁ ClN ₂ O ₆ 457.11 457.2 8 -OH -OCH ₃ H C ₂₂ H ₂₁ ClN ₂ O ₆ 445.11 445.2 9 -OH Cl H C ₂₁ H ₁₈ Cl ₂ N ₂ O ₅ 449.06 450.3 10 -OH -CH (CH _{3) 2} H C ₂₄ H ₂₅ ClN ₂ O ₅ 457.15 457.4 11 -OH - (CH _{2) 2} CH ₃ H C ₂₄ H ₂₅ ClN ₂ O ₅ 457.15 457.4 12 -OH -CH ₂ -CH (CH ₃ ) ₂ H C ₂₅ H ₂₇ ClN ₂ O ₅ 471.16 471.4 13 -OH -C (OH) (CH ₃ ) ₂ H C ₂₄ H ₂₅ ClN ₂ O ₆ 473.14 472.8 14 -OH -C (CH _{3) 3} H C ₂₅ H ₂₇ ClN ₂ O ₅ 471.16 470.8

7. (2R, 4R) -4-[(3-acetyl-isoxazole-5-carbonyl) -amino] -5- (3'-chlorobiphenyl-4-yl) -2-hydroxy-pentanoic acid

8. (2R, 4R) -5 (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-methoxy-isoxazole-5-carbonyl) -amino] -phen Carbonic acid

9. (2R, 4R) -5 (3'-Chloro-biphenyl-4-yl) -4-[(3-chloro-isoxazole-5-carbonyl) -amino] -2-hydroxy-phene Carbonic acid

10. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(3-isopropyl-isoxazole-5-carbonyl) -amino]- Pentanic acid

11. (2R, 4R) -5 (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(3-propyl-isoxazole-5-carbonyl) -amino] -phen Carbonic acid

12. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(3-isobutyl-isoxazole-5-carbonyl) -amino]- Pentanic acid

13. (2R, 4R) -5 (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-{[3- (1-hydroxy-1-methyl-ethyl) -isoxazole -5-carbonyl] -amino} -pentanoic acid

14. (2R, 4R) -4-[(3-tert-butyl-isoxazole-5-carbonyl) -amino] -5- (3'-chloro-biphenyl-4-yl) -2-hydroxy -Pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 15 -OH 2-Chlorophenyl H C ₂₇ H ₂₂ Cl ₂ N ₂ O ₅ 525.09 525.4 16 -OH 2-hydroxyphenyl H C ₂₇ H ₂₃ ClN ₂ O ₆ 507.12 507.2

15. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -4-{[5- (2-chlorophenyl) -isoxazole-3-carbonyl] -amino} -2- Hydroxy-pentanoic acid

16. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-{[5- (2-hydroxyphenyl) -isoxazole-3-carbonyl] -Amino} -pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 17 -OH 2-hydroxy-phenyl H C ₂₇ H ₂₄ ClN ₃ O ₅ 506.14 506.0 18 -OCH ₂ CH ₃ 2-hydroxy-phenyl H C ₂₉ H ₂₈ ClN ₃ O ₅ 534.17 534.2 19 -OH

H C ₂₅ H ₂₂ ClN ₅ O ₄ 492.14 492.2 20 -OCH ₂ CH ₃

H C ₂₇ H ₂₆ ClN ₅ O ₄ 520.17 520.2 21 -OCH ₂ -CH (CH ₃ )

H C ₂₉ H ₃₀ ClN ₅ O ₄ 548.20 548.2 22

H C ₃₀ H ₂₆ ClN ₅ O ₇ 604.15 604.1 23 -OH

H C ₂₆ H ₂₃ ClN ₄ O ₄ 491.14 491.2 24 -OCH ₂ CH ₃

H C ₂₈ H ₂₇ ClN ₄ O ₄ 519.17 519.2 25 -OCH ₂ -CH (CH ₃ )

H C ₃₀ H ₃₁ ClN ₄ O ₄ 547.20 547.1 26 -OCH (CH ₃ )

H C ₂₉ H ₂₉ ClN ₄ O ₄ 533.19 533.2 27 -OH

H C ₂₈ H ₂₄ Cl ₂ N ₄ O ₅ 567.11 567.1 28 -OCH ₂ CH ₃

H C ₃₀ H ₂₈ Cl ₂ N ₄ O ₅ 595.14 595.1 29 -OCH ₂ -CH (CH ₃ )

H C ₃₂ H ₃₂ Cl ₂ N ₄ O ₅ 623.18 623.2 30 -OCH (CH ₃ )

H C ₃₁ H ₃₀ Cl ₂ N ₄ O ₅ 609.16 609.2 31 -OH

H C ₂₉ H ₂₇ ClN ₄ O ₆ 563.16 563.2 32 -OH -CH (OH) -CH ₃ H C ₂₃ H ₂₄ ClN ₃ O ₅ 458.14 458.4 33 -OCH ₂ CH ₃

C ₂₈ H ₂₇ ClN ₄ O ₄ 519.17 519.4

17. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-{[5- (2-hydroxy-phenyl) -2H-pyrazole-3- Carbonyl] -amino} -pentanoic acid (TFA salt)

18. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-{[5- (2-hydroxy-phenyl) -2H-pyrazole-3- Carbonyl] -amino} -pentanoic acid ethyl ester (TFA salt)

19. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazole-3-carbonyl) -Amino] -pentanoic acid (TFA salt)

20. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid ethyl ester

21. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid isobutyl ester

22. (2S, 4S) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester (TFA salt)

23. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -Amino] -pentanoic acid (TFA salt)

24. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid ethyl ester

25. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid isobutyl ester

26. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid isopropyl ester

27. (2R, 4R) -4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -5- (3'-chlorobiphenyl-4-yl) 2-hydroxy-pentanoic acid (TFA salt)

28. (2R, 4R) -4-{[5- (2-Chloro-benzoylamino) -2H-pyrazole-3-carbonyl] -amino} -5- (3'-chloro-biphenyl-4- Yl) -2-hydroxy-pentanoic acid ethyl ester (TFA salt)

29. (2R, 4R) -4-{[5- (2-Chloro-benzoylamino) -2H-pyrazole-3-carbonyl] -amino} -5- (3'-chloro-biphenyl-4- I) -2-hydroxy-pentanoic acid isobutyl ester (TFA salt)

30. (2R, 4R) -4-{[5- (2-Chloro-benzoylamino) -2H-pyrazole-3-carbonyl] -amino} -5- (3'-chloro-biphenyl-4- Yl) -2-hydroxy-pentanoic acid isopropyl ester (TFA salt)

31. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-{[5- (2-methoxy-benzoylamino) -2H-pyrazole- 3-carbonyl] -amino} -pentanoic acid

32. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-{[5- (1-hydroxy-ethyl) -2H-pyrazole-3 -Carbonyl] -amino} -pentanoic acid

33. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-3-yl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid ethyl ester (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 34 -OH

H C ₂₆ H ₂₃ ClN ₄ O ₄ 491.14 491.2 35 -OH -OH -CH ₃ C ₂₂ H ₂₂ ClN ₃ O ₅ 444.12 444.4 36 -OCH ₂ -CH (CH ₃ ) -OH -CH ₃ C ₂₆ H ₃₀ ClN ₃ O ₅ 500.19 500.0 37 -OH -OH

C ₂₆ H ₂₃ ClN ₄ O ₅ 507.14 506.8 38 -OH -OH 2-fluoro-phenyl C ₂₇ H ₂₃ ClFN ₃ O ₅ 524.13 523.8 39 -OH -OH 3-chloro-phenyl C ₂₇ H ₂₃ Cl ₂ N ₃ O ₅ 540.10 539.6 40 -OH -OCH ₂ -CH ₃ H C ₂₃ H ₂₄ ClN ₃ O ₅ 458.14 458.4

34. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-3-yl-1 H-pyrazole-3-carbonyl) -Amino] -pentanoic acid (TFA salt)

35. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-hydroxy-l-methyl-lH-pyrazole-3-car Carbonyl) -amino] -pentanoic acid

36. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-hydroxy-l-methyl-lH-pyrazole-3-car Carbonyl) -amino] -pentanoic acid isobutyl ester

37. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-hydroxy-1-pyridin-2-yl-1 H-pyrazole 3-carbonyl) -amino] -pentanoic acid (TFA salt)

38. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (2-fluoro-phenyl) -5-hydroxy-1 H-pyrazole-3 -Carbonyl] -amino} -2-hydroxy-pentanoic acid

39. (2R, 4S) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (3-chloro-phenyl) -5-hydroxy-1 H-pyrazole-3- Carbonyl] -amino} -2-hydroxy-pentanoic acid

40. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-[(5-ethoxy-1 H-pyrazole-3-carbonyl) -amino] -2-hydrate Roxy-pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 41 -OH = O Phenyl C ₂₇ H ₂₄ ClN ₃ O ₅ 506.14 506.2 42 -OH = O 3-chlorophenyl C ₂₆ H ₂₂ Cl ₂ N ₄ O ₅ 541.10 540.6 43 -OH = O 2-Chlorophenyl C ₂₆ H ₂₂ Cl ₂ N ₄ O ₅ 541.10 540.6 44 -OH = O 4-fluorophenyl C ₂₆ H ₂₂ ClFN ₄ O ₅ 525.13 524.8

41. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-2,5-dihydro-1 H-pyra Sol-3-carbonyl) -amino] -pentanoic acid (TFA salt)

42. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (3-chloro-phenyl) -5-oxo-4,5-dihydro-1 H -[1,2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid

43. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (2-chloro-phenyl) -5-oxo-4,5-dihydro-1 H -[1,2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid

44. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (4-fluoro-phenyl) -5-oxo-4,5-dihydro- 1H- [1,2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 45 -OH -CF ₃ H C ₂₁ H ₁₈ ClF ₃ N ₄ O ₄ 483.10 483.0

45. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-trifluoromethyl-4H- [1,2,4] triazole 3-carbonyl) -amino] -pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 46 -OH Cl H C ₂₀ H ₁₈ Cl ₂ N ₄ O ₄ 449.07 449.0

46. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -4-[(5-chloro-lH- [1,2,4] triazole-3-carbonyl) -amino ] -2-hydroxy-pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 47 -OH = O Phenyl C ₂₆ H ₂₃ ClN ₄ O ₅ 507.14 507.2

47. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H- [ 1,2,4] triazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 48 -OH = O benzyl C ₂₉ H ₂₆ ClN ₃ O ₅ 532.16 532.2 49 -OH = O Phenyl C ₂₈ H ₂₄ ClN ₃ O ₅ 518.14 518.2

48. (2R, 4R) -4-[(1-benzyl-6-oxo-1,6-dihydro-pyridazine-3-carbonyl) -amino] -5- (3'-chlorobiphenyl-4 -Yl) -2-hydroxy-pentanoic acid (TFA salt)

49. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(6-oxo-1-phenyl-1,6-dihydro-pyridazine- 3-carbonyl) -amino] -pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value Measures 50 -OH -OH H C ₂₂ H ₂₀ ClN ₃ O ₅ 442.11 442.0

50. (2R, 4R) -5 (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(6-hydroxy-pyridazine-3-carbonyl) -amino] -phen Carbonic Acid (TFA Salt)

Example 19

Following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, compounds having the following formula were prepared as parent compounds.

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ b R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH H -OH 2 2 ', 5'-diCl C ₂₀ H ₁₈ Cl ₂ N ₄ O ₅ 465.07 465.2 2 -OCH ₂ -CH (CH ₃ ) ₂ H -OH 2 2 ', 5'-diCl C ₂₄ H ₂₆ Cl ₂ N ₄ O ₅ 521.13 521.2 3 -OCH- (CH ₃ ) ₂ H -OH 2 2 ', 5'-diCl C ₂₃ H ₂₄ Cl ₂ N ₄ O ₅ 507.11 507.2 4 -O-CH ₂ CH ₃ H -OH 2 2 ', 5'-diCl C ₂₂ H ₂₂ Cl ₂ N ₄ O ₅ 493.10 493.2 5 -O- (CH ₂ ) ₆ -CH ₃ H -OH 2 2 ', 5'-diCl C ₂₇ H ₃₂ Cl ₂ N ₄ O ₅ 563.18 563.2 6 -OH H -OH 2 2'-F, 5'-Cl C ₂₀ H ₁₈ ClFN ₄ O ₅ 449.10 449.2 7 -OCH ₂ -CH (CH ₃ ) ₂ H -OH 2 2'-F, 5'-Cl C ₂₄ H ₂₆ ClFN ₄ O ₅ 505.16 505.2 8 -OCH- (CH ₃ ) ₂ H -OH 2 2'-F, 5'-Cl C ₂₃ H ₂₄ ClFN ₄ O ₅ 491.14 491.4 9 -O-CH ₂ CH ₃ H -OH 2 2'-F, 5'-Cl C ₂₂ H ₂₂ ClFN ₄ O ₅ 477.13 477.0 10 -O- (CH ₂ ) ₆ -CH ₃ H -OH 2 2'-F, 5'-Cl C ₂₇ H ₃₂ ClFN ₄ O ₅ 547.20 547.2 11 -OCH- (CH ₃ ) ₂ H -O-CH ₂ OC (O) -CH- (CH ₃ ) ₂ -NH ₂ 2 2'-F, 5'-Cl C ₂₉ H ₃₅ ClFN ₅ O ₇ 620.22 620.0 12 -OH H -OH 2 2'-CH _3, 5'-Cl C ₂₁ H ₂₁ ClN ₄ O ₅ 445.12 445.4 13 -OCH ₂ -CH (CH ₃ ) ₂ H -OH 2 2'-CH _3, 5'-Cl C ₂₅ H ₂₉ ClN ₄ O ₅ 501.18 501.4 14 -OCH- (CH ₃ ) ₂ H -OH 2 2'-CH _3, 5'-Cl C ₂₄ H ₂₇ ClN ₄ O ₅ 487.17 487.4 15 -O-CH ₂ CH ₃ H -OH 2 2'-CH _3, 5'-Cl C ₂₃ H ₂₅ ClN ₄ O ₅ 473.15 473.2 16 -O- (CH ₂ ) ₆ -CH ₃ H -OH 2 2'-CH _3, 5'-Cl C ₂₈ H ₃₅ ClN ₄ O ₅ 543.23 543.4 17 -OH H -OH One 2'-OCH ₃ C ₂₁ H ₂₂ N ₄ O ₆ 427.15 427.2

1. (2R, 4R) -5 (2 ', 5'-dichlorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] tria Sol-4-carbonyl) -amino] -pentanoic acid

2. (2R, 4R) -5 (2 ', 5'-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] Triazole-4-carbonyl) -amino] -pentanoic acid isobutyl ester

3. (2R, 4R) -5 (2 ', 5'-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] Triazole-4-carbonyl) -amino] -pentanoic acid isopropyl ester

4. (2R, 4R) -5 (2 ', 5'-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] Triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester

5. (2R, 4R) -5 (2 ', 5'-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] Triazole-4-carbonyl) -amino] -pentanoic acid heptyl ester

6. (2R, 4R) -5 (5'-Chloro-2'-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3 ] Triazole-4-carbonyl) -amino] -pentanoic acid

7. (2R, 4R) -5 (5'-Chloro-2'-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3 ] Triazole-4-carbonyl) -amino] -pentanoic acid isobutyl ester

8. (2R, 4R) -5 (5'-Chloro-2'-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3 ] Triazole-4-carbonyl) -amino] -pentanoic acid isopropyl ester

9. (2R, 4R) -5- (5'-Chloro-2'-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3 ] Triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester

10. (2R, 4R) -5- (5'-Chloro-2'-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3 ] Triazole-4-carbonyl) -amino] -pentanoic acid heptyl ester

11. (2R, 4R) -4-{[1- ( (S) -2-amino-3-methyl-butyryloxymethoxy) -1H- [1,2,3] triazole-4-carbonyl ] -Amino} -5- (5'-chloro-2'-fluoro-biphenyl-4-yl) -2-hydroxy-pentanoic acid isopropyl ester

12. (2R, 4R) -5- (5'-Chloro-2'-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2, 3] triazole-4-carbonyl) -amino] -pentanoic acid

13. (2R, 4R) -5 (5'-Chloro-2'-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2, 3] triazole-4-carbonyl) -amino] -pentanoic acid isobutyl ester

14. (2R, 4R) -5- (5'-Chloro-2'-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2, 3] triazole-4-carbonyl) -amino] -pentanoic acid isopropyl ester

15. (2R, 4R) -5- (5'-Chloro-2'-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2, 3] triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester

16. (2R, 4R) -5- (5'-Chloro-2'-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2, 3] triazole-4-carbonyl) -amino] -pentanoic acid heptyl ester

17. (2R, 4R) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino] -5- (2'-meth Methoxy-biphenyl-4-yl) -pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ b R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures 18 -OH H -OCH ₂ OC (O) -CH ₃ 2 2'-F, 5'-Cl C ₂₃ H ₂₂ ClFN ₄ O ₇ 521.12 521.1

18. (2R, 4R) -4-[(3-acetoxymethoxy-3H- [1,2,3] triazole-4-carbonyl) -amino] -5- (5'-chloro-2 ' -Fluoro-biphenyl-4-yl) -2-hydroxy-pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ b R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures 19 -OH -OCH ₃ H 2 2'-F, 5'-Cl C ₂₂ H ₂₀ ClFN ₂ O ₆ 463.10 463.2

19. (2R, 4R) -5- (5'-Chloro-2'-fluoro-biphenyl-4-yl) -2-hydroxy-4-[(3-methoxy-isoxazole-5-car Carbonyl) -amino] -pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ³ R ⁴ b R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures 20 -OH = O Phenyl 2 2'-F, 5'-Cl C ₂₆ H ₂₂ ClFN ₄ O ₅ 525.13 525.2

20. (2R, 4R) -5- (5'-Chloro-2'-fluoro-biphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-4,5 -Dihydro-1H- [1,2,4] triazole-3-carbonyl) -amino] -pentanoic acid

-XR ³ R ⁴ =

Ex. R ¹ R ⁴ b R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures 21 -OH -OCH ₂ OC (O) -CH ₃ 2 2 ', 5'-diCl C ₂₇ H ₂₄ Cl ₂ N ₄ O ₇ 587.10 587.1 22 -OCH ₂ CH- (CH ₃ ) ₂ -OCH ₂ OC (O) CH- (CH ₃ ) ₂ NH ₂ One 3'-Cl C ₃₄ H ₄₀ ClN ₅ O ₇ 666.26 666.0

21. (2R, 4R) -4-[(3-acetoxymethoxy-3H-benzotriazole-5-carbonyl) -amino] -5- (2 ', 5'-dichloro-biphenyl-4- Yl) -2-hydroxy-pentanoic acid

22. (2R, 4R) -4-{[3-( (S) -2-Amino-3-methyl-butyryloxymethoxy) -3H-benzotriazole-5-carbonyl] -amino} -5 -(3'-Chloro-biphenyl-4-yl) -2-hydroxy-pentanoic acid isobutyl ester

Example 20

Following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, compounds having the following formulas were prepared as parent compounds or TFA salts.

-XR ³ R ⁴ =

Ex. R ³ R ⁴ R ⁵ The MS m / z : [M + H] < ⁺ > Calculated value Measures One H H Cl C ₂₀ H ₁₉ ClN ₄ O ₄ 415.11 415.4

1. (2R, 4R) -5 (3-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(1H- [1,2,3] triazole-4-carbonyl) -amino ] -Pentanoic acid (TFA salt)

-XR ³ R ⁴ =

Ex. R ³ R ⁴ R ⁵ The MS m / z : [M + H] < ⁺ > Calculated value Measures One H H Cl C ₂₀ H ₁₉ ClN ₄ O ₄ 415.11 415.2

2. (2R, 4R) -5 (3-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) -amino ] -Pentanoic acid

-XR ³ R ⁴ =

Ex. R ³ R ⁴ R ⁵ The MS m / z : [M + H] < ⁺ > Calculated value Measures 3 = O 3-chlorophenyl Cl C ₂₆ H ₂₂ Cl ₂ N ₄ O ₅ 541.10 541.2 4 = O Phenyl Cl C ₂₆ H ₂₃ ClN ₄ O ₅ 507.14 507.2

3. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -4-{[1- (3-chloro-phenyl) -5-oxo-4,5-dihydro-1 H- [1,2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid

4. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1 H- [ 1,2,4] triazole-3-carbonyl) -amino] -pentanoic acid

-XR ³ R ⁴ =

Ex. R ³ R ⁴ R ⁵ The MS m / z : [M + H] < ⁺ > Calculated value Measures 5 -C (O) N (CH ₃ ) ₂ H Cl C ₂₄ H ₂₅ ClN ₄ O ₅ 485.15 486.2 6 -C (O) N (CH ₃ )-[(CH ₂ ) ₂ OCH ₃ ] H Cl C ₂₆ H ₂₉ ClN ₄ O ₆ 529.18 529.2 7 -C (O) -CH ₃ H Cl C ₂₃ H ₂₂ ClN ₃ O ₅ 456.12 456.2 8

H Cl C ₂₆ H ₂₃ ClN ₄ O ₄ 491.14 491.2 9

H Cl C ₂₆ H ₂₃ ClN ₄ O ₄ 491.14 493.2

5. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -4-[(5-dimethylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2- Hydroxy-pentanoic acid

6. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-({5-[(2-methoxy-ethyl) -methyl-carbamoyl] -2H-pyrazole-3-carbonyl} -amino) -pentanoic acid

7. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) -amino] -5- (3-chloro-biphenyl-4-yl) -2-hydroxy- Pentanic acid

8. (2R, 4R) -5 (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-3-yl-2H-pyrazole-3-carbonyl) -Amino] -pentanoic acid (TFA salt)

9. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -Amino] -pentanoic acid (TFA salt)

Example 21

Following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, compounds having the following formula were prepared as parent compounds.

-XR ³ R ⁴ =

Ex. R ³ R ⁴ R ⁵ R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures One H H Cl Cl C ₂₀ H ₁₈ Cl ₂ N ₄ O ₄ 449.07 449.0

1. (2R, 4R) -5 (3,3'-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl ) -Amino] -pentanoic acid

-XR ³ R ⁴ =

Ex. R ³ R ⁴ R ⁵ R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures 2 -CH ₂ OCH ₃ H Cl Cl C ₂₃ H ₂₃ Cl ₂ N ₃ O ₅ 492.10 492.2

2. (2R, 4R) -5- (3,3'-dichloro-biphenyl-4-yl) -2-hydroxy-4-[(5-methoxymethyl-2H-pyrazole-3-carbonyl ) -Amino] -pentanoic acid

Production Example 13

(2R, 4R) -5- (4- Bromophenyl ) -2-hydroxy-4-[(3-hydroxy-3H- Benzotriazole -5-carbonyl) -amino] - Pentanoic acid  Ethyl ester

HCTU (837 mg, 2.0 mmol) is added to a 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (362 mg, 2.0 mmol) solution and the mixture is 10 minutes at room temperature. Was stirred. Then DIPEA (529 μL, 3.0 mmol) and (2R, 4R) -4-amino-5- (4-bromophenyl) -2-hydroxy-pentanoic acid ethyl ester (320 mg, 1.0 mmol) were added The resulting mixture was stirred at rt for 15 min. The mixture was concentrated in vacuo and the resulting residue was purified (C18 column, 55 g, 20-70% MeCN in water with 5% TFA) to give the title compound (365 mg) as a white solid.

Example 22

(2R, 4R) -5- (5'- Chloro -2'- Fluorobiphenyl -4-yl) -2-hydroxy-4 - [(3-hydroxy- Benzotriazole -5-carbonyl) -amino] - Pentanoic acid

^{SilicaCat ® DPP-Pd; (2R} , 4R) of (0.3 mmol / g loading 37.4 mg, 10 μmol) in ethanol (500 ㎕) and water (150 ㎕) -5- (4- bromophenyl) -2-hydroxy Hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid ethyl ester (50.0 mg, 105 μmol), phenyl boronic acid (157 μmol, 1.5 eq.) And To a solution of K ₂ CO ₃ (43.4 mg, 314 μmol) was added and the reaction mixture obtained was heated at 100 ° C. for 10 minutes. The resulting mixture was cooled to room temperature, then 1.0 M LiOH (838 μl, 838 μmol) in water was added and the mixture was stirred for 30 minutes. The mixture was filtered, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (17.9 mg; purity 98%). MS m / z [M + H] ⁺ for C ₂₄ H ₂₀ ClFN ₄ O ₅ , calculated 499.11. Found 499.2.

Example 23

Following the procedure described in the Examples herein and substituting the appropriate starting materials and reagents, compounds having the following formulas were prepared as parent compounds or TFA salts.

Ex. R ¹ a R ⁶ The MS m / z : [M + H] < ⁺ > Calculated value Measures One -OH One 3'-CH ₃ C ₂₅ H ₂₄ N ₄ O ₅ 461.17 461.2 2 -OH 2 2'-CH _3, 5'-Cl C ₂₅ H ₂₄ ClN ₄ O ₅ 496.14 495.2 3 -OH One 2'-OCH ₃ C ₂₅ H ₂₄ N ₄ O ₆ 477.17 477.2 4 -OH 2 2 ', 5'-diCl C ₂₄ H ₂₀ Cl ₂ N ₄ O ₅ 515.08 515.0 5 -OCH ₂ CH ₃ 2 2 ', 5'-diCl C ₂₆ H ₂₄ Cl ₂ N ₄ O ₅ 543.11 543.2 6 -OCH ₂ CH (CH ₃ ) ₂ 2 2 ', 5'-diCl C ₂₈ H ₂₈ Cl ₂ N ₄ O ₅ 571.14 571.2 7 -OCH (CH ₃ ) ₂ 2 2 ', 5'-diCl C ₂₇ H ₂₆ Cl ₂ N ₄ O ₅ 557.13 557.1 8 -OH 2 3'-Cl, 5'-OH C ₂₄ H ₂₁ ClN ₄ O ₆ 497.12 497.2

1. (2S, 4S) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -5- (3'-methyl-biphenyl-4- Sun) -pentanoic acid

2. (2S, 4S) -5- (5'-Chloro-2'-methyl-biphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-1 H-benzotriazole-5 -Carbonyl) -amino] -pentanoic acid

3. (2S, 4S) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -5- (2'-methoxy-biphenyl-4 -Working) -pentanoic acid

4. (2S, 4S) -5- (2 ', 5'-dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl ) -Amino] -pentanoic acid

5. (2R, 4R) -5- (2 ', 5'-dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl ) -Amino] -pentanoic acid ethyl ester

6. (2R, 4R) -5- (2 ', 5'-dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl ) -Amino] -pentanoic acid isobutyl ester

7. (2R, 4R) -5- (2 ', 5'-dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl ) -Amino] -pentanoic acid isopropyl ester (TFA salt)

8. (2S, 4S) -5- (3'-Chloro-5'-hydroxy-biphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole- 5-carbonyl) -amino] -pentanoic acid

Production Example 14

(S) -2- (l-biphenyl-4-yl-l- Methyl ethyl ) -5-oxo- Pyrrolidine -One- Carboxylic acid t - butyl ester

To a solution of 2- (4-bromophenyl) acetonitrile (130.0 g, 0.7 mol) and iodomethane (103.9 mL, 1.7 mol) in THF (1.0 L), NaH (60% dispersion in mineral oil, 66.7 g, 1.7 mol) was added in small portions at 10 ° C. After the addition was completed, the obtained mixture was stirred at 10 ° C. for 2 hours. The mixture was poured into ice water (2.0 L) and extracted with EtOAc (1.5 L). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous MgSO ₄ and concentrated to afford compound 1 (175 g, including mineral oil) as a yellow oil, which was used directly without further purification. _{^{1 H NMR (CDCl 3, 300}} MHz) δ7.52 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 1.72 (s, 6H).

To a solution of Compound 1 (175 g, containing mineral oil) in DCM (1.0 L), DIBAL (1.0 M solution in DCM, 700 mL, 0.70 mol) was added dropwise at -78 ° C. The resulting reaction mixture was stirred at −78 ° C. for 1.5 h and then quenched carefully with 3.0 N HCl (1.0 L). The resulting mixture was stirred at rt overnight, the organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ and concentrated to afford compound 2 (180 g) as a yellow oil, which was used directly without further purification. ¹ H NMR (CDCl ₃ , 300 MHz) δ9.48 (s, 1H), 7.53 (d, J = 11.0 Hz, 2H), 7.17 (d, J = 11.0 Hz, 2H), 1.46 (s, 6H).

To an aqueous solution of NaCN (32.7 g, 0.7 mol) in 1.0 L of H ₂ O, (NH ₄ ) ₂ CO ₃ (380 g, 4.0 mol) and Compound 2 (180 g) were added. The reaction mixture obtained was refluxed overnight and then concentrated at 75 ° C. under reduced pressure. Water (350 mL) was added to the residue and the obtained mixture was concentrated again. The residue was suspended in petroleum ether (700 mL) and water (250 mL) and the resulting mixture was stirred at rt for 15 min. The precipitate was collected by filtration and dried to give 3 (150 g) as a white solid. ^{1 H NMR (DMSO-d6,} 300 MHz) δ10.39 (s, 1H), 8.05 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H) , 4.17 (s, 1 H), 1.42 (s, 3 H), 1.34 (s, 3 H).

A suspension of compound 3 (150 g, 0.51 mol) in 6.0 N NaOH (400 mL) and ethane-1,2-diol (300 mL) was stirred at 120 ° C. for 38 h. The resulting mixture was cooled to room temperature and neutralized with HCl solution. The precipitate was collected by filtration and dried to give compound 4 (250 g, containing NaCl salt) as a white solid. ^{1 H NMR (DMSO-d6,} 300 MHz) δ7.35 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 3.22 (s, 1H), 1.16 (s, 3H) , 1.15 (s, 3 H).

To a suspension of compound 4 (250 g, including NaCl salt) in MeOH (1.0 L), thionylchloride (72.0 mL, 1.0 mol) was added dropwise at 5 ° C. The resulting mixture was refluxed overnight and the solvent was removed under reduced pressure. The residue was partitioned between DCM (1.0 L) and saturated aqueous NaHCO ₃ solution (1.5 L). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ and concentrated to afford the corresponding methyl ester (90.0 g). 2-phenylacetyl chloride (48.6 g, 0.32 mol) was added dropwise at 0 ° C. to a solution of ester (90.0 g) and Et ₃ N (56.5 mL, 0.41 mol) in DCM (1.0 L) and obtained. The resulting mixture was stirred at 0 ° C. for 30 minutes. The mixture was washed with 1.0 N HCl (500 mL) and saturated aqueous NaCl solution, respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 5 (120 g). _{^{1 H NMR (CDCl 3, 300}} MHz) δ7.32 (m, 5H), 7.18 (m, 2H), 6.95 (m, 2H), 5.68 (br s, 1H), 4.76 (d, J = 9.0 Hz, 1H), 3.57 (s, 3H), 3.53 (d, J = 5.0 Hz, 2H), 1.30 (s, 3H), 1.25 (s, 3H).

To a solution of compound 5 (120 g, 0.30 mol) in MeOH (500 mL) was added 4.0 N NaOH (200 mL). The resulting mixture was stirred at rt for 4 h, then the pH was adjusted to pH = 1 with 3.0 N HCl. The resulting mixture was extracted with EtOAc (2x300 mL). The combined extracts were washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was recrystallized from EtOAc / hexanes to give compound 6 (82.0 g). ^{1 H NMR (DMSO-d6,} 300 MHz) δ7.41 (d, J = 6.0 Hz, 2H), 7.22 (m, 5H), 6.99 (d, J = 6.0 Hz, 2H), 4.65 (d, J = 3H), 1.30 (s, 3H). ≪ RTI ID = 0.0 > 1H), 3.52 (d, J = 14.0 Hz, 1H), 3.36 (d, J = 14.0 Hz,

A suspension of compound 6 (82.0 g, 0.21 mol) in distilled water (3.0 L) was adjusted to pH = 8.5 with 3.0 N LiOH and a clear solution was formed. Immobilized Penicillinase (20.0 g) was added and the resulting mixture was stirred at 37 ° C. for 60 hours. The mixture was filtered, the filtrate was adjusted to pH = 1 with 3.0 N HCl and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated to give compound 7 (59.0 g, containing 80% ee, 2-phenylacetic acid).

A suspension of compound 7 (59.0 g, containing 2-phenylacetic acid) in 6.0 N HCl (500 mL) was refluxed overnight. The resulting mixture was washed with EtOAc (300 mL) and the aqueous phase was concentrated under reduced pressure to afford the corresponding amino acid as its hydrochloride salt. The salt was dissolved in water (300 mL) and the solution obtained was adjusted to pH = 11. A solution of (Boc) ₂ O (33.0 g, 0.2 mol) in acetone (200 mL) was added and the resulting mixture was stirred at rt for 2 h. The mixture was washed with hexane (200 mL) and the aqueous phase adjusted to pH = 2. The resulting mixture was extracted with EtOAc (2x300 mL). The combined extracts were washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated to afford compound 8 (37.0 g) as a white solid. _{^{1 H NMR (CDCl 3, 300}} MHz) δ9.48 (br s, 1H), 7.46 (d, J = 7.0 Hz, 2H), 7.26 (d, J = 7.0 Hz, 2H), 5.02 (br s, 1H ), 4.56 (d, J = 9.0 Hz, 1H), 1.39 (s, 9H).

A mixture of 1.0 NK ₂ CO ₃ (200 mL) and compound 8 (37.0 g, 0.1 mol) in dioxane (200 mL) was degassed with nitrogen for 30 minutes, followed by phenylboronic acid (13.4 g, 0.1 mol) and Pd (PPh ₃ ) ₄ (1.6 g, 1.4 mmol) were added. The resulting mixture was heated at 75 ° C. for 8 hours and then cooled to room temperature. The mixture was washed with EtOAc / hexanes (150 mL, 1: 1), the aqueous phase was adjusted to pH = 2 and extracted with EtOAc (2 × 300 mL). The combined extracts were washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated to afford compound 9 (31.0 g, 84% yield) as a white solid.

A solution of compound 9 (31.0 g, 84 mmol), meldric acid (13.3 g, 92 mmol) and DMAP (15.4 g, 0.13 mol) in DCM (400 mL) was cooled to -5 ° C and DCM (200 mL) A solution of DCC (19.0 g, 92 mmol) was added over 1 hour. The resulting mixture was stirred at -5 ° C overnight. The precipitate was removed by filtration and the filtrate was washed with 1.0 N HCl (2 × 700 mL) and saturated aqueous NaCl solution, respectively. The organic layer containing compound 10 was dried over anhydrous MgSO _{4 and} then used directly in the next step without concentration.

A solution of compound 10 in DCM (600 mL) was cooled to -5 ° C and AcOH (45.0 mL) was added. Then NaBH ₄ (7.0 g, 0.2 mol) was added in small portions over 30 minutes and the resulting mixture was stirred at -5 ° C for 3 hours. Water (50.0 mL) was added dropwise, followed by saturated aqueous NaCl solution (450 mL). The organic layer was washed with water (2x300 mL) and saturated aqueous NaHCO ₃ solution (2x300 mL), dried over anhydrous MgSO ₄ and concentrated to afford compound 11 (32.0 g, 75% ee) as an off-white solid. It was. After recrystallization from ethanol, asymmetrically pure compound 11 (13.0 g) was obtained. ¹ H NMR (CDCl ₃ , 300 MHz)? 7.61 (m, IH), 4.46 (br s, IH), 4.26 (s, 3H), 1.76 (s, 3H), 1.48 (s, 6H), 1.39 (s, 9H).

A solution of compound 11 (13.0 g, 27.0 mmol) in toluene (100.0 mL) was refluxed for 3 hours. After evaporation of the solvent, the residue was recrystallized from hexanes / EtOAc (3: 1) to give the title compound (8.0 g) as a white solid.

Production Example 15

(2R, 4S) Amino-5-biphenyl-4-yl-2-hydroxy-5- Methylhexanoic acid  Ethyl ester

(S) -2- (1-biphenyl-4-yl-1-methylethyl) -5-oxo-pyrrolidine-1-carboxylic acid t -butyl ester in 3.0 N HCl-EtOAc (14.0 g, 36.9 mmol, racemic) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give compound 1 (10.0 g) as a white solid.

To a solution of compound 1 (10.0 g, 35.8 mmol) in THF (80.0 mL), BuLi (2.5 M in hexane, 15.0 mL) was added dropwise at -78 ° C. After the obtained mixture was stirred for 30 minutes, pivaloyl chloride (4.8 mL, 39.4 mmol) was added dropwise. The mixture was stirred at −78 ° C. for 1 hour and then quenched with saturated aqueous NH ₄ Cl solution. The resulting mixture was extracted with EtOAc and the combined extracts were washed with saturated aqueous NaCl solution, dried over anhydrous MgSO ₄ , and concentrated. The residue was purified by flash column chromatography on silica gel to give compound 2 (9.0 g) as a white solid.

To a solution of compound 2 (9.0 g, 24.7 mmol) in THF (50.0 mL), sodium bis (trimethylsilyl) amide (2.0 M in THF, 18.5 mL, 37.0 mmol) was added dropwise at -78 ° C. The resulting mixture was stirred for 20 minutes and a solution of oxaziridine derivative (10.8 g, 37.0 mmol) in THF (30.0 mL) was added dropwise. The mixture was stirred at 78 ° C. for 30 minutes and then quenched with saturated aqueous NH ₄ Cl solution. The resulting mixture was extracted with EtOAc (1.0 L) and the extract was washed with 1.0 N HCl and saturated aqueous NaCl solution, dried over anhydrous MgSO ₄ and evaporated to remove most solvent. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (DCM: hexane = 1: 1 to DCM) to give compound 3 (4.3 g, racemic). This racemate was subjected to chiral AD-column chromatography to give pure chiral compound 3 (1.4 g). ^{1 H NMR (DMSO-d6,} 300 MHz) δ7.63 (m, 4H), 7.49 (m, 4H), 4.83 (d, 1H), 3.29 (m, 1H), 2.31 (m, 2H), 1.40 ( s, 3H), 1.36 (s, 3H), 1.28 (s, 9H). LC-MS (ESI): m / z 380.1 [M + H] < + >.

A solution of compound 3 (1.7 g, 160 mmol) in ethanol (15.0 mL) and 12.0 N HCl (15.0 mL) was heated at 90-95 ° C. for 20 hours. The solvent was removed and the residue was treated with 3.0 N HCl-ethanol solution (25.0 mL) under reflux for 3 hours. After removal of the solvent, the residue was purified by preparative HPLC to give the title compound (0.6 g) which was a foamy solid HCL salt. ¹ H NMR (DMSO-d 6, 300 MHz) δ 7.88 (br s, 3H), 7.68 (m, 4H), 7.49 (m, 4H), 7.35 (m, 1H), 6.11 (br s, 1H), 4.11 (br s, 1H), 4.05 (q, 2H), 3.61 (br s, 1H), 1.67 (m, 2H),, 1.40 (s, 3H), 1.36 (s, 3H), 1.09 (t, 3H ). LC-MS (ESI): m / z 342.1 [M + H] < + >.

Example 24

5-[(S) -2-biphenyl-4-yl-1-((R) -2- Carboxy -2-hydroxy-ethyl) -2- methyl - Propylcarbamoyl ] -1H- Pyrazole -3- Carboxylic acid

(2R, 4S) -4-Amino-5-biphenyl-4-yl-2-hydroxy-5-methyl-hexanoic acid ethyl ester (70 mg, 0.2 mmol), 3,5-pyrazoledicarboxylic acid (32 mg, 0.2 mmol), and HCTU (85 mg, 0.2 mmol) were combined in DMF (5 mL) and stirred for 2 minutes. DIPEA (79 mg, 0.6 mmol) was added and the resulting mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was evaporated under reduced pressure. The crude material was dissolved in ethanol and sufficient equivalents of 10N NaOH were added to make the mixture basic. The reaction was carefully monitored over 1 hour until the final deprotection was complete. The mixture was then reoxidized with equal volume of acetic acid and evaporated under reduced pressure. The product was purified using reverse phase chromatography (10-70% MeCN gradient) to give the title compound (14 mg; purity 90%) as a TFA salt. MS m / z [M + H] ⁺ for C ₂₄ H ₂₅ N ₃ O ₆ , calculated 452.17; Found 452.2

Example 25

Following the procedure described herein and substituting the appropriate starting materials and reagents, a compound having the formula was prepared as a parent compound or TFA salt.

Ex. -XR ³ R ⁴ The MS m / z : [M + H] < ⁺ > Calculated value found One

C ₂₂ H ₂₄ N ₄ O ₄ 409.18 409.4 2

C ₂₂ H ₂₄ N ₄ O ₅ 425.17 425.2 3

C ₂₃ H ₂₄ N ₂ O ₆ 425.16 425.2

1. (2R, 4S) -5-Biphenyl-4-yl-2-hydroxy-5-methyl-4-[(1H- [1,2,3] triazole-4-carbonyl) -amino] -Hexanoic acid (TFA salt)

2. (2R, 4S) -5-Biphenyl-4-yl-2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino ] -5-Methyl-hexanoic acid (TFA salt)

3. (2R, 4S) -5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxy-isoxazole-5-carbonyl) -amino] -5-methyl-hexanoic acid

Analysis 1

Human and rat NEP  And human ACE in  In vitro assays for quantification of inhibitory activity

Inhibitory activity of the compounds in human and murine neprilysin (EC 3.4.24.11; NEP) and human angiotensin converting enzyme (ACE) was measured using in vitro assays as described below.

Rat kidney ( kidney )from NEP  Extraction of active

Rat NEP was obtained from the kidneys of adult Sprague Dawley rats. Whole kidneys are washed in cold phosphate buffered saline (PBS), ice-cold lysis buffer (1% Triton X-114, 150 mM NaCl, 50 mM tri (hydroxymethyl) aminomethane (Tris) pH 7.5; Bordier (1981) J. Biol . Chem . 256: 1604-1607), at a rate of 5 mL per gram of kidney. Samples were homogenized on ice using polytron hand held tissue grinder. Homogenate was centrifuged at 1000 × g in a swinging bucket rotor at 3 ° C. for 5 minutes. The pellet was resuspended in 20 mL of ice cold lysis buffer and incubated for 30 minutes on ice. The sample is then layered onto 25 mL of ice cold cushion buffer (6% w / v sucrose, 50 mM pH 7.5 Tris, 150 mM NaCl, 0.06%, Triton X-114), 3- Heated to 37 ° C. for 5 minutes and centrifuged at 1000 × g with a swing bucket rotor for 3 minutes at room temperature. The two upper layers were aspirate off and a viscous oily precipitate containing the concentrated membrane fraction was obtained. Glycerol was added to a concentration of 50% and the sample was stored at -20 ° C. Protein concentration was quantified using a BCA detection system, based on bovine serum albumin (BSA).

Enzyme inhibition assay

Recombinant human NEP and recombinant human ACE were commercially obtained (R & D Systems, Minneapolis, Minn., Catalog numbers 1182-ZN and 929-ZN, respectively). (Dnp) -OH (Medeiros et al. (1997) Braz . J. Med . Biol . Res. 30: 1157-62; Anaspec, San Jose, Calif.). And Abz-Phe-Arg-Lys (Dnp) -Pro-OH (Araujo et al. (2000) Biochemistry 39: 8519-8525; Bachem, Torrance, CA) were used for NEP and ACE analysis, respectively.

The assay was performed with assay buffer (NEP: 50 mM HEPES, pH 7.5, 100 mM NaCl, 0.01% polyethylene glycol sorbitan monolaurate (Tween-20), 10 μΜ ZnSO ₄ ; ACE: 50 mM HEPES, pH 7.5, 100 mM NaCl, 0.01% Tween-20, 1 μM ZnSO ₄ ) was performed at 37 ° C. in 384-well white opaque plates using a fluorescence peptide substrate at a concentration of 10 μM.

The test compounds were analyzed over a concentration range of 10 [mu] M to 20 pM. Test compounds were added to the enzyme and incubated at 37 ° C. for 30 minutes prior to starting the reaction by addition of the substrate. The reaction was terminated by adding glacial acetic acid to a final concentration of 3.6% (v / v) after 20 minutes of incubation at 37 ° C.

Plates were read on a fluorometer with excitation and emission wavelengths set at 320 nm and 405 nm, respectively. Inhibition constants were obtained by nonlinear regression of data using the following equation (GraphPad Software, Inc., San Diego, Calif.):

v = v ₀ / [1 + ( I / K ' )]

Where v is the rate of reaction, v ₀ is the rate of inhibition, I is the inhibitor concentration, and K ' is the apparent inhibition constant.

The compounds of the invention were tested with this assay and confirmed to have the following pK _i values in human NEP. In general, prodrug compounds did not inhibit this enzyme in vitro assays or did not test prodrugs because activity was not expected (nd).

nd = not determined

Analysis 2

Anesthetized In rats ACE  And NEP  For active Pharmacokinetics ( Pharmacodynamic , PD ) analysis

Male, Sprague Dawley, and normal blood pressure mice were anesthetized with 120 mg / kg (ip) of inactin. Once anesthetized, the jugular vein, carotid artery (PE 50 tubing) and bladder PE 50 tubing catheter cannulate and tracheotomy (Teflon) Needle, size 14 gauge) and spontaneous respiration. Animals are then allowed to settle for 60 minutes and continue to inject 5 mL / kg / h saline (0.9%) to maintain hydration and produce urine. Body temperature is maintained by the use of a heating pad during the experiment. After a 60 minute settling time, animals are administered 2 doses of AngI (1.0 μg / kg for ACE inhibitor activity) at 15 minute intervals (iv). 15 minutes after the second dose of AngI, the vehicle is treated with a vehicle or test compound. After 5 minutes, the animals are further treated with a bolus iv injection of atrial natriuretic peptide (ANP; 30 μg / kg). Start urine collection (with pre-weighted eppendorf tube) immediately after ANP treatment and continue for 60 minutes. At 30 and 60 minutes for urine collection, animals are re-challenged with AngI. Blood pressure measurements are made using a Notocord system (Kalamazoo, MI). Urine samples are frozen at −20 ° C. until used for cGMP analysis. Urine cGMP concentration is measured by Enzyme Immuno Assay using a commercial kit (Analysis Designs, Ann Arbor, Michigan, Cat. No. 901-013). Urine volume is measured gravimetrically. Urine cGMP output is calculated as the product of urine output and urine cGMP concentration. ACE inhibition is assessed by quantifying the percent inhibition of the pressor response to AngI. NEP inhibition is assessed by quantifying the enhancement of ANP-induced elevations in urine cGMP output.

Analysis 3

Hypertensive Conscious SHR  Model of antihypertensive effect Invivo  evaluation

When spontaneously hypertensive rats (SHR, 14-20 weeks of age) had free access to feed and water, they were allowed to acclimate for at least 48 hours when they reached the test site. For blood pressure recordings, animals are implanted with a small rodent radiotransmitter (telemetry unit); DSI Models TA11PA-C40 or C50-PXT, Data Science Inc., USA. The tip of the catheter connected to the transmitter is inserted into the descending aorta above the iliac bifurcation and secured in position with tissue adhesive. The transmitter was kept intraperitoneally, fixed to the abdominal wall, and the abdominal incision was closed with a non-absorbable suture. The outer skin is closed with sutures and staples. Allow the animals to recover with appropriate postoperative care. On the day of the experiment, the animals in the cage were placed on top of the telemetry receiver unit to adapt to the test environment and baseline recording. Baseline measurements are performed after at least 2 hours, then animals are administered a vehicle or test compound, and blood pressure measurements are performed up to 24 hours after administration. Data is recorded continuously during the study using Notocord software (Kalamazoo, MI) and stored as an electronic digital signal. Measured parameters are blood pressure (shrinkage, diastolic and mean arterial blood pressure) and heart rate.

Analysis 4

Hypertensive Conscious DOCA In vivo Evaluation of Antihypertensive Effects in a Rat-Salt Rat Model

CD rats (male, adult, 200-300 grams, US Charles River Laboratory) are allowed to reach the test site prior to placing on a high salt diet, giving a minimum of 48 hours of acclimation time. One week after the start of the high salt diet (8% in feed or 1% NaCl in drinking water), deoxycorticosterone acetate (DOCA) pellets (100 mg, release time of 90 days, Innovative Research of America, Sarasota, FL) is implanted subcutaneously and unilateral nephrectomy is performed. At this time, animals are also surgically implanted with small rodent radiotransmitters to measure blood pressure (see Analysis 3 for details). Allow the animals to recover with appropriate postoperative care. Study design, data recording and measured parameters are similar to those described in analysis 3.

Analysis 5

Hypertensive Conscious Dahl / SS  In vivo Evaluation of Antihypertensive Effect in Rat Model

Male, Dahl salt sensitive rats (Dahl / SS, 6-7 week old rats of Charles River Laboratory, USA) were placed in the test site prior to placement on 8% NaCl high salt diet (TD.92012, Harlan, USA). After arrival, allow at least 48 hours of acclimation time and then surgically implant a small rodent radiotransmitter to measure blood pressure (see Analysis 3 for details). The animals were allowed to recover with appropriate postoperative care. About four to five weeks after the onset of the high salt diet, the animals are expected to become hypertensive. Once the high blood pressure level is identified, the animals are used for the study while continuing the high salt diet to maintain that high blood pressure level. The study design, data recording and measured parameters are similar to those described in analysis 3.

While the invention has been described in terms of specific embodiments or embodiments thereof, it will be understood by those skilled in the art that various changes may be made or equivalents may be made without departing from the true spirit and scope of the invention. In addition, to the extent permitted by applicable patent laws and regulations, all documents, patents, and patent applications cited herein are hereby incorporated by reference in their entirety to the same extent as if each document were incorporated herein by reference in its entirety. do.

Claims (30)

Claims 1. Compounds of the general formula < RTI ID = 0.0 > (I) < / RTI &

In the formula:
R ¹ is selected from -CR ⁷ and -NR ⁸ R ⁹ ;
R ² is H or -P (O) (OH) ₂ or R ² forms -CR ¹⁸ R ¹⁹ -with R ⁷ or -C (O)-with R ⁸ ;
X is -C _{1 - 9} heteroaryl;
R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -NO ₂ ; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl optionally substituted with methyl; Thiophenyl optionally substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl; When R ³ is present it is bonded to a carbon atom;
R ⁴ is absent or H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -OCH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -OCH ₂ OC (O) CH ₃ ; -CH ₂ OP (O) (OH) ₂ ; -CH ₂ CH (OH) CH ₂ OH; _{-CH [CH (CH 3) 2} ] -NHC (O) OC 1-6 alkyl; Pyridinyl; And phenyl or benzyl optionally substituted with one or more groups selected from halo, -COOR ³⁵ , -OCH ₃ , -OCF ₃ , and -SCF ₃ ; When R ⁴ is present it is bonded to a carbon or nitrogen atom;
Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- ;
a is 0 or 1; R ⁵ is selected from halo, —CH ₃ , —CF ₃ , and —CN;
b is 0 or an integer of 1 to 3; Each R ⁶ is independently selected from halo, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ ;
R ⁷ is H, -C _{1 - 8} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - _{[(CH 2) 2 O]} 1-3 CH 3, -C 1 - 6 alkylene group ^{-OC (O) R 10, -C} 1 - 6 alkylene _{^{-NR 12 R 13, -C 1 -}} 6 alkylene- ^{C (O) R 31, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

,

, And

≪ / RTI >
R ¹⁰ is -C _{1 - 6} alkyl, -OC _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -OC _{3 - 7} cycloalkyl, phenyl, -O- ^{phenyl, -NR 12 R 13, -CH [} CH _{(CH 3) 2] -NH 2} , -CH [CH (CH 3) 2] -NHC (O) OC 1 - 6 alkyl, and -CH (NH ₂₎ CH ₂ COOCH ₃ is selected from; R ¹² and R ¹³ are independently selected from H, -C _{1 - 6,} or selected from alkyl, and benzyl; Or R ¹² and R ¹³ together form — (CH ₂ ) _3-6 —, —C (O) — (CH ₂ ) ₃ — or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —; R ³¹ is -OC _{1 - 6} is selected from alkyl, -O- benzyl, and -NR ¹² R ^13; R ³² is -C _{1 - 6} alkyl, -C _{0 - 6} alkylene -C _{6 - 10} aryl;
R ⁸ is selected from H, —OH, —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, -pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ¹⁴ is H, -C ₁₆ alkyl, -C _{6 - 10} aryl, -OCH ₂ -C _{6 - 10} aryl, -CH ₂ OC _{6 - 10} aryl, and is selected from -NR ¹⁵ R ^16; R ¹⁵ and R ¹⁶ are independently selected from H and -C _{1 -} is selected from _4-alkyl;
R ⁹ is H, -C _{1 - 6} alkyl, and -C (O) is selected from -R ^17; R ¹⁷ is H, -C _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -C _{6 - 10} aryl, and -C _{1 - 9} is selected from heteroaryl;
R ¹⁸ and R ¹⁹ are independently H, -C _{1 -} to form a _seven or selected from cycloalkyl, or R ¹⁸ and R ¹⁹ together are = O _{- 6} alkyl, and -OC _3;
R ²⁰ is selected from H and -C _{1 - 6} alkyl is selected from;
R ²¹ and R ³⁵ are independently selected from H, -C _{1 - 6} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7 cycloalkyl, - [(CH 2) 2} O] 1-3 CH 3, -C 1 - 6 alkylene group ^{-OC (O) R 25, -C} 1 - 6 alkylene -NR ²⁷ R ^28, -C _{1 - 6} alkylene ^{-C (O) R 33, -C} 0 - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

,

, And

≪ / RTI >
R ²⁵ is -C _{1 - 6} alkyl, -OC _{1 - 6} alkyl, -C _{3 - 7} cycloalkyl, -OC _{3 - 7} cycloalkyl, phenyl, -O- ^{phenyl, -NR 27 R 28, -CH [} CH _{(CH 3) 2] -NH 2} , -CH [CH (CH 3) 2] -NHC (O) OC 1 - 6 is selected from alkyl, and _{-CH (NH 2) CH 2 COOCH} 3; R ²⁷ and R ²⁸ are independently selected from H, -C _{1 - 6,} or selected from alkyl, and benzyl; Or R ²⁷ and R ²⁸ together form — (CH ₂ ) _3-6 —, —C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —; R ³³ is -OC _{1 - 6} alkyl, -O- benzyl, and -NR ²⁷ R ²⁸ is selected from; R ³⁴ is -C _{1 - 6} alkyl, -C _{0 - 6} alkylene -C _{6 - 10} aryl;
R ²² and R ²³ are independently selected from H, -C _{1 - 6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH, - (CH 2) 2 OCH 3, - (CH 2) 2 SO 2 NH 2, _{- (CH 2) 2 N (} CH 3) 2, -C 0 - 1 alkylene -C _{3 - 7} cycloalkyl, and - (CH _{2) 2} -, or already selected from thiazolyl; Or R ²² and R ²³ together is halo, -OH, -COOH, or optionally substituted saturated or partially unsaturated with -CONH ₂ -C _{3 -} to form a _{5-heterocyclic;} Optionally including an oxygen atom in the ring;
R ²⁴ is -C _{1 - 6} alkyl; -C _{0 - 1} alkylene -OC _{1 - 6} alkyl; Phenyl optionally substituted with halo or -OCH ₃ ; And -C _{1 - 9} is selected from heteroaryl;
R ³⁶ is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl;
Each alkyl group of R ¹ , R ³ , and R ⁴ is optionally substituted with 1 to 8 fluorine atoms; And;
Methylene linking group on the biphenyl is one or two -C _{1 - 6} alkyl group is optionally substituted by or cyclopropyl. The compound of claim 1, wherein X is pyrazole, imidazole, triazole, benzotriazole, furan, pyrrole, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thia Diazole, pyridazine, pyridine, pyrimidine, pyran, benzimidazole, benzoxazole, benzothiazole, pyridylimidazole, and pyridyltriazole. The compound of claim 2, wherein X is pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxa Compound selected from sol, pyridylimidazole, and pyridyltriazole. The compound of claim 3, wherein

≪ / RTI > The compound of claim 1, wherein R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is H, R ⁸ is H or —OH, and R ⁹ is H . The compound of claim 1, wherein R ¹ is —OR ⁷ ; R ⁷ is -C _{1 - 8} alkyl, -C _1-3 alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - [( _{CH 2) 2 O] 1-3 CH} 3, -C 1 -6 alkylene group ^{-OC (O) R 10, -C} 1 - 6 alkylene _{^{-NR 12 R 13, -C 1 -}} 6 alkylene -C ( _{^{O) R 31, -C 0 -}} 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

,

, And

; or
R ¹ is —NR ⁸ R ⁹ ; R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ⁹ is H; or
R ¹ is —NR ⁸ R ⁹ ; R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; R ⁹ is -C _{1 - 6} alkyl or -C (O) R ¹⁷ a;
R ¹ is —NR ⁸ R ⁹ ; R ⁸ is selected from H and -OH; R ⁹ is -C _{1 - 6} is selected from alkyl, and -C (O) R ^17;
R ¹ is —OR ⁷ and R ² together with R ⁷ form —CR ¹⁸ R ¹⁹ —; or
R ¹ is —NR ⁸ R ⁹ , and R ² together with R ⁸ form —C (O) —. A method according to any one of claims 1 to 4, wherein R ¹ is -OR ^7, R ⁷ is H, -C _{1 - 8} alkyl, -C _1-6 alkylene ^{-OC (O) R 10, -C} 0 - ₆ alkylene-morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, and

≪ / RTI >
R ¹⁰ is -OC _{3 - 7} cycloalkyl-alkyl; R ³² is -CH ₃ . The compound of any one of claims 1-4, wherein R ¹ is —NR ⁸ R ⁹ , R ⁸ is H, and R ⁹ is H. ⁶ . The compound of any one of claims 1-8, wherein R ² is H. 10. The compound of claim 1, wherein R ³ is absent or H; Halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -NO ₂ ; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl optionally substituted with methyl; Thiophenyl optionally substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl; R ²¹ is H. Of claims 1 to 9. A method according to any one of the preceding, R ³ is -C _{0 - 1} alkylene and -COOR ^21; R ²¹ is -C _1-6 alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - [( _{CH 2) 2 O] 1-3 CH} 3, -C 1 - 6 alkylene group ^{-OC (O) R 25, -C} 1 - 6 alkylene _{^{-NR 27 R 28, -C 1 -}} 6 alkylene -C ( _{^{O) R 33, -C 0 -}} 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

,

, And

≪ / RTI > The compound of claim 1, wherein R ³ is absent or H; Halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl substituted with methyl; Thiophenyl substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl; R ²⁰ is -C _{1 - 6} alkyl; R ²¹ is selected from H and -C _{1 - 6} alkyl is selected from; R ²² is selected from H and -C _{1 - 6} alkyl is selected from; And R ²³ is H, -C _{1 - 6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH, - (CH 2) 2 OCH 3, - (CH 2) 2 N (CH 3) 2, -C _{3 - 7} cycloalkyl, and - (CH _{2) 2} -, or already selected from thiazolyl; Or R ²² and R ²³ together form azetidine, pyrrolidine, piperidine or morpholine, optionally substituted with -OH or -CONH ₂ ; R ²⁴ is -C _{1 - 6} alkyl; -C _{0 - 1} alkylene -OC _{1 - 6} alkyl; Phenyl substituted with halo or -OCH ₃ ; And pyridine. The compound of any one of claims 1-12, wherein R ⁴ is absent or H; -OH; -C _1-6 alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; And phenyl or benzyl optionally substituted with one or more groups selected from halo, -COOR ³⁵ , -OCH ₃ , -OCF ₃ , and -SCF ₃ ; R ³⁵ is H. The compound of claim 1, wherein R ⁴ is —OCH ₂ OC (O) CH ₃ ; -CH ₂ OP (O) (OH) ₂ ; -C _{1 - 2} alkylene -COOR ^35; And phenyl or benzyl substituted with one or more -COOR ³⁵ groups; Wherein R ³⁵ is -C _{1 - 6} alkyl, -C _{1 - 3} alkylene -C _{6 - 10} aryl, -C _{1 - 3} alkylene -C _{1 - 9} heteroaryl, -C _{3 - 7} cycloalkyl, - [ _{(CH 2) 2 O] 1-3} CH 3, -C 1 - 6 alkylene group ^{-OC (O) R 25, -C} 1 - 6 alkylene _{^{-NR 27 R 28, -C 1 -}} 6 alkylene -C _{^{(O) R 33, -C 0}} - 6 alkylene morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl,

,

,

, And

≪ / RTI > The compound of any one of claims 1-12, wherein R ⁴ is absent or H; -OH; -C _1-6 alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; Phenyl optionally substituted with one halo group; And benzyl optionally substituted with one or more groups selected from halo, -COOH, -OCH ₃ , -OCF ₃ , and -SCF ₃ ; R ³⁵ is H; R ³⁶ is —CH (CH ₃ ) ₂ ; Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- . The compound of claim 1, wherein a is 0; Or a is 1 and R ⁵ is 3-chloro. The compound of claim 1, wherein b is 0; Or b is 1 and R ⁶ is 3'-chloro, 3'-methyl, or 2'-methoxy; Or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy , Compound. 18. The compound of any of claims 1-17, wherein the methylene linker on biphenyl is substituted with two methyl groups. The compound of claim 1, wherein R ¹ is —OR ⁷ ; R ⁷ is H, -C _{1 - 8} alkyl, -C _{1 - 6} alkylene group ^{-OC (O) R 10, -C} 0-6 alkylene-morpholinyl, -C _{1 - 6} alkylene -SO ₂ -C _{1 - 6} alkyl, and

≪ / RTI >
R ¹⁰ is -OC _{3 - 7} cycloalkyl; R ³² is —CH ₃ ; R ⁸ is H; R ⁹ is H;
R ² is H;
X is pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridyl Midazole, and pyridyltriazole;
R ³ is absent or H; Halo; -C _{0 - 5} alkylene -OH; -NH ₂ ; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _{1 - 6} alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, -CF ₃ , -OCH ₃ , -NHC (O) CH ₃ , and phenyl; Naphthalenyl; Pyridinyl; Pyrazinyl; Pyrazolyl substituted with methyl; Thiophenyl substituted with methyl or halo; Furanyl; And -CH ₂ -morpholinyl;
R ⁴ is absent or H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; Phenyl optionally substituted with one halo group; And benzyl optionally substituted with one or more groups selected from halo, -COOH, -OCH ₃ , -OCF ₃ , and -SCF ₃ ;
Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- ;
a is 0; Or a is 1 and R ⁵ is 3-chloro;
b is 0; Or b is 1 and R ⁶ is 3'-chloro, 3'-methyl, or 2'-methoxy; Or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy ;
R ²⁰ is -C _{1 - 6} alkyl;
R ²¹ is selected from H and -C _{1 - 6} alkyl is selected from;
R ²² is selected from H and -C _{1 - 6} alkyl is selected from; R ²³ is H, -C _{1 - 6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH, - (CH 2) 2 OCH 3, - (CH 2) 2 N (CH 3) 2, -C 3 _{- 7} cycloalkyl, and - (CH _{2) 2} -, or already selected from thiazolyl; Or R ²² and R ²³ together form azetidine, pyrrolidine, piperidine or morpholine, optionally substituted with -OH or -CONH ₂ ;
R ²⁴ is -C _{1 - 6} alkyl; -OC _{1 - 6} alkyl; -CH ₂ -OC _{1 - 6} alkyl; Phenyl substituted with halo or -OCH ₃ ; And pyridinyl;
R ³⁵ is H;
R ³⁶ is —CH (CH ₃ ) ₂ ;
The methylene linkage on biphenyl is optionally substituted with two methyl groups. The method according to claim 1,
R ¹ is -OR ⁷ ;
R ² is H;
X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole;
R ³ is H; Halo; -C _{0 - 5} alkylene -OH; -C _{1 - 6} alkyl; -CF _3; -C _{3 - 7} cycloalkyl; -C _{0 - 2} alkylene -OC _1-6 alkyl; -C (O) R ²⁰ ; -C _{0 - 1} alkylene -COOR ^21; -C (O) NR ²² R ²³ ; -NHC (O) R ²⁴ ; = O; -C (CH ₃ ) = N (OH); Phenyl optionally substituted with one or two groups independently selected from halo, -OH, and -OCH ₃ ; Pyridinyl; Pyrazinyl; And thiophenyl substituted with methyl or halo;
R ⁴ is H; -OH; -C _{1 - 6} alkyl; -C _{1 - 2} alkylene -COOR ^35; -CH ₂ CH (OH) CH ₂ OH; Pyridinyl; And phenyl optionally substituted with one halo group; Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3- ;
a is 0; Or a is 1 and R ⁵ is 3-chloro;
b is 0; Or b is 1 and R ⁶ is 3'-chloro, 3'-methyl, or 2'-methoxy; Or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy ;
R ²⁰ is -C _{1 - 6} alkyl;
R ²¹ is H;
R ²² is selected from H and -C _{1 - 6} alkyl is selected from; R ²³ is -C _{1 - 6 alkyl, - (CH 2) 2 OCH} 3, and -C _{3 - 7} cycloalkyl or selected from; Or R ²² and R ²³ together form azetidine, pyrrolidine, or piperidine, both of which are optionally substituted with -OH or -CONH ₂ ;
R ² is halo or phenyl substituted with -OCH ₃ ;
R ³⁵ is H;
The methylene linking group on biphenyl is optionally substituted with two methyl groups. A method of preparing a compound according to claim 1, comprising coupling a compound of formula 1 to a compound of formula 2 to produce a compound of formula I:

Wherein P ¹ is an amino-protecting group selected from H or t -butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t -butyldimethylsilyl ; The method further comprises the step of deprotecting the compound of formula 1 when P ¹ is an amino protecting group. Intermediates or salts thereof useful for the synthesis of a compound according to any one of claims 1 to 20 having the formula

Wherein P ¹ is an amino-protecting group selected from H or t -butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t -butyldimethylsilyl . A method of preparing a compound according to any one of claims 1 to 20, comprising deprotecting a compound or salt thereof selected from:

,

,

, And

.
Wherein R ^1P is selected from —OP ³ , —NHP ² , and —NH (OP ⁴ ); R ^3P is -C _{0 - 1} is selected from alkylene -COO-P ^3, and ⁴ -OP phenyl substituted with _{- 5} alkylene -OP ^4, -C _0; R ^4P is -OP ⁴ ; -C _{1 -2} alkylene -COO-P ^3; And phenyl or benzyl substituted with -COO-P ³ ; P ² is t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonylamino ethoxycarbonyl, formyl, trimethylsilyl, and t-butyl dimethyl silyl group selected from amino-protecting group; P ³ is a carboxy-protecting group selected from methyl, ethyl, t -butyl, benzyl, p -methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t -butyldimethylsilyl, and diphenylmethyl; P ⁴ is -C _{1 - 6} alkyl, tri C _{1- 6} alkyl silyl, -C _{1 - 6} alkanoyl, benzoyl, benzyl, p - methoxybenzyl, 9-fluorenyl methyl, and diphenyl selected from methylhydroxy And a loxyl-protecting group. Useful intermediates or salts thereof for the synthesis of compounds according to any one of claims 1 to 20, wherein:

,

,

, And

,
Wherein R ^1P is selected from —OP ³ , —NHP ² , and —NH (OP ⁴ ); R ^3P is -C _{0 - 5} is selected from alkylene -OP ^4, -C _0-1 alkylene -COO-P ^3, and -OP ⁴ phenyl substituted by; R ^4P is -OP ⁴ ; -C _{1 - 2} alkylene -COO-P ^3; And phenyl or benzyl substituted with -COO-P ³ ; P ² is t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonylamino ethoxycarbonyl, formyl, trimethylsilyl, and t-butyl dimethyl silyl group selected from amino-protecting group; P ³ is a carboxy-protecting group selected from methyl, ethyl, t -butyl, benzyl, p -methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t -butyldimethylsilyl, and diphenylmethyl; P ⁴ is -C _{1 - 6} alkyl, tri C _{1 - 6} alkyl silyl, -C _{1 - 6} alkanoyl, benzoyl, benzyl, p - methoxybenzyl, 9-fluorenyl methyl, and diphenyl selected from methylhydroxy The intermediate being a loxyl-protecting group. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. The method of claim 25, wherein the adenosine receptor antagonist, α-adrenergic receptor antagonist, β ₁ -adrenergic receptor antagonist, β ₂ -adrenergic receptor agonist, dual-acting β-adrenergic receptor antagonist / α ₁ -receptor antagonist, final Glycation product inhibitors (AGE breakers), aldosterone antagonists, aldosterone synthase inhibitors, aminoptidases N inhibitors, androgens, angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzymes / neprilysine inhibitors, angiotensin-converting enzyme 2 activations Agents and stimulants, angiotensin-II vaccines, anticoagulants, anti-diabetics, antidiabetics, antiglaucoma, anti-lipids, antinociceptive agents, thrombolytics, AT ₁ receptor antagonists and dual-acting AT ₁ receptor antagonists / Neprilysin inhibitors and multifunctional angiotensin receptor blockers, bradykinin receptor antagonists, calcium channel blockers, kinase inhibitors, di Renal, diuretic, dopamine agonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, HMG-CoA reductase inhibitors, estrogens, estrogen receptor agonists and / or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and Analogs thereof, natriuretic peptide removal receptor antagonists, neprilysin inhibitors, nitric oxide donors, non-steroidal anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterase inhibitors, Further comprising a therapeutic agent selected from prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blockers, soluble guanylate cyclase stimulators and activators, tricyclic antidepressants, vasopressin receptor antagonists, and combinations thereof Pharmaceutical composition. The method according to claim 26, wherein the therapeutic agent is a pharmaceutical composition of the AT ₁ receptor antagonist. A compound according to any one of claims 1 to 20 for use in therapy. The compound of claim 28 for use in the treatment of hypertension, heart failure, or kidney disease. Use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of hypertension, heart failure, or kidney disease.